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BIOC3800 / BIOL5211 / BIOL5231 Lectures 2011: Dr. J.A. Illingworth

Sensory Transducers

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Table of contents

We are having some problems with the Blackboard VLE, so sets of lecture slides can now be downloaded from this website. Please go to the relevant lectures (below) and then click the download link. I normally update these slide sets with additional recently published material shortly before each lecture is delivered.

• introduction and general advice

• lecture one: negative feedback and bacterial chemotaxis

• lecture two: primary cilia and TRP proteins

• lecture three: taste and smell

• lecture four: vision

• lecture five: hearing

• lecture six: mechanotransducers, glucose and oxygen sensing

• supplementary material: control systems

• references

Introduction:

This course will focus on the biochemical processes that convert information from the internal and external environments into hormonal or neuronal signals. In addition to the intracellular signal transduction pathways, the course will include transducer evolution, organogenesis, dynamic range, adaptation to ongoing stimuli, and selective filtering of irrelevant information by the transducing cells. Sensors will be considered in relation to their downstream processing systems and the biological effectiveness of the overall feedback loop. Much of the literature is concerned with mammals, but relevant examples from invertebrates, plants and bacteria will be included where appropriate.

Sensory impairment is a significant human problem that affects a large proportion of the population at some stage in their lives. Technological advances and better understanding of the underlying mechanisms can help with this. Consider especially the plight of those with a double sensory impairment, such as the patient who provided this account. There is a local Leeds charity operating from Shire View in Headingley that tries to assist such people in Leeds.

Textbooks: Much of this material has been discovered in the last five years, some of it in the last few months. It takes several years to prepare and publish a textbook, so you won't find a truly up-to-date accounts of sensory transducer biochemistry in most popular texts. What you will find are some excellent accounts and diagrams of the underlying anatomy and physiology. The following books are available in multiple copies from the Leeds University Library and they are all very good:

• Principles of Anatomy and Physiology. Tortora GJ & Derrickson BH (Wiley, 2008.) ISBN 9780470233474 there is a simple account in chap. 17, older editions are also useful

• Medical Physiology. Boron WF and Boulpaep EL (eds) (W.B. Saunders, 2005.) ISBN 1416023283 more detail in chap. 13

• Human Physiology. Sherwood L (Brooks/Cole, 2010) ISBN 9780495826293 see chapter 6 on special senses

• Principles of Neural Science. Kandel ER et al (McGraw-Hill, 2000.) ISBN 0838577016 see part V - this is an excellent book, but it is getting dated

• Fundamental Neuroscience. Squire LR et al (Academic Press, 2008.) ISBN 9780123740199 detailed account in chapters 24 - 27

Physiology texts tend to focus on the downstream processing within the central nervous system, but our course concentrates on the initial transducers and their immediate neighbours.

How much work should I do? This is an open-ended course so it is important to know when to stop. The University recommends about 150 hours study for a 20 credit module such as this. This topic is 16% of the course, which corresponds to 24 hours in total, or about 3 hours private study for each 1 hour lecture. Most of this time will be spent reading original papers and reviews. Don't get bogged down in detail, and don't try to memorise enormous lists of genes or protein folding motifs. It is sufficient to know that there are lots of them!

I am revising the references on this website. Over the years we have accumulated far too many, and some of the older ones are out of date. I am aiming for a much simpler system in the future with many fewer papers, but for the time being you will find both the old and the new systems in use.

In the lecture summaries, some of the papers are highlighted in red. These are either important seminal papers or they have particularly good diagrams or explanations. You should concentrate on these. For each sensor, try to understand how it works, and how it adapts to gradual changes in the input signal. Focus on the diagrams and summaries in the papers, not on the "materials & methods". It is better to know a little about lots of sensors rather than enormous detail about one or two, but there is no need to cover every one.

Examinations: What do you need to know? This is a rapidly expanding field, where new papers are being published faster than your lecturer can read them. In these circumstances we will not set nit-picking examination questions that focus on a single tiny aspect, or rely on reading one particular paper, or knowing one particular experimental technique. Expect "broad brush" questions where you can select the aspects that you want to cover, and where there will be opportunities to compare different species and different sensory modalities. It won't matter if you have forgotten some of this course, but don't expect to waffle through if you have forgotten ALL of it!

Exam question 2005: "Discuss with examples the biochemical mechanisms responsible for sensory adaptation."

Download the 2005 marking scheme.

Exam question 2006: "Discuss the roles of motor proteins in sensory transduction and adaptation."

Download the 2006 marking scheme.

Exam question 2007: "Discuss the roles of primary cilia in sensory transduction."

Download the 2007 marking scheme.

Exam question 2008: "Discuss the biological importance of sensory adaptation and outline the adaptation mechanisms in a variety of biological transducers."

Download the 2008 marking scheme.

Exam question 2009: "Describe with examples how the basic molecular architecture of primary cilia and microvilli has been adapted to create a wide range of sensory transducers."

Download the 2009 marking scheme.

Exam question 2010: "Compare and contrast the signal transduction mechanisms in sense organs that monitor the external world with those that monitor the internal condition of the body. Please illustrate your answer with some specific examples."

Download the 2010 marking scheme.

The exam question in 2011 will follow a generally similar pattern to those set in previous years. When revising, make sure that you cover a good spread of topics, although we do not expect you to remember every last detail about all of them.

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Concentrate on the mechanisms responsible for key features of biological transducers:

Sensory transducers report biologically relevant information to their owners.

Sensors monitoring the external environment often:

• are very fast

• are very sensitive

• adapt to ongoing stimuli

• have a huge dynamic range

• incorporate local feedback loops

• report changes rather than the steady state

• select and filter information from the beginning of the pathway

• convert from analog signals to faster, low-noise digital encoding at an early stage of the transduction pathway

Sensors monitoring the internal environment usually:

• have more time

• require less sensitivity

• respond in a narrow physiological range

• show less adaptation towards ongoing situations

• often form part of "whole body" negative feedback systems

• have less need to filter the raw information to remove unwanted noise

• are more likely to include slower analog systems rather than faster digital signalling components

Compare and contrast...

High performance ‘external’ sensors		Slower, less adaptive ‘internal’ mechanisms
Vision		Taste (plus a family of closely-related gut content sensors expressed by entero-endocrine cells lower down the GI tract that rarely reach consciousness)
Hearing and balance
Smell (very high sensitivity for an enormous range of ligands)
Mechanosensors (some of these are slow, but muscle spindles and pressure transducers may provide rapid and precise responses to external events.)		Monitoring systems for oxygen, carbon dioxide, glucose, small molecules and ions, temperature, osmolarity and fluid flow have limited dynamic range and respond more slowly to stimulation.

Students should also be prepared to put the transduction pathways in a biological context: how did these systems evolve, how are they constructed during organogenesis, and how are they related to the overall biological fitness of the organism?

There is an excellent open access review by Stephan Frings (2009) Primary processes in sensory cells: current advances. J Comp Physiol A 195, 1–19.

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Lecture one

Sensory adaptation. Biological significance of changes in signals rather than static levels. Importance of negative feedback and integration in achieving a wide dynamic range. Methyl-accepting bacterial chemotaxis proteins as a prokaryotic example. Vertebrate TRP receptors for heat and cold. Depolarisation. Cross reactivity with capsaicin and menthol.

Download lecture one slides

Negative feedback

Certain fundamental features are common to all closed-loop control systems, which are illustrated below. Every closed loop system keeps a controlled variable C as close as possible to some reference value R despite interference by an external load L which disturbs the result. In order to achieve its objective the control system subtracts C from R so as to generate an error signal, E. This error signal regulates the flow of material or energy M into the controlled system so as to minimise E and compensate for the effects of the external load.

Every closed loop system needs a reference value which provides a target to aim for. This is true even for biological control systems, although sometimes the targets are obscure. There is no requirement for the target to stay constant, although they often do.

• constant reference value but varying load: room thermostat

• varying reference but constant load: audio amplifier

• varying reference and varying load: muscles

Biological reference values may be genetically determined, for example through the amino acid sequences of regulatory proteins, which define their binding constants for allosteric effectors. Behavioural targets for an organism might also reflect the genetically programmed "wiring diagram" for the central nervous system.

For sensory transducers the reference value is very definitely NOT constant, because it is the input signal from the outside world. The transducer will commonly track this varying input signal, and thereby generate first derivative and filtered information more appropriate to the needs of the organism.

Bacterial chemotaxis

The key concept is that bacteria are too small to sense chemical gradients directly (they would detect the same concentration back and front) so the only way that they can discover the best direction of travel is to make small random movements in arbitrary directions, and to keep going for longer if things are are getting better.

E. coli cells have typically half a dozen flagellae, distributed over the surface of the cell. Each flagellum can be independently rotated by a motor in the cell wall, and is attached to the cell by an extremely flexible universal joint. The flagellae are "handed" like corkscrews. If they all rotate anti-clockwise (viewed from the far end) then they can mesh together and form an efficient propulsive unit, but if one or more adopt a clockwise rotation the whole bundle flies apart and the cell tumbles randomly in the growth medium.

The "classical" chemosensory system is based on periplasmic ligand binding proteins which interact with methyl-accepting chemotaxis proteins (MCPs) plugged through the bacterial inner membrane. If the attractant concentration falls, the MCPs induce autophosphorylation of CheA, which in turn leads to phosphorylation of CheY and CheB. CheY switches the drive motor to clockwise mode (favouring tumbling) and CheB strips methyl groups from the MCPs, increasing their sensitivity to attractant ligands.

The effect is that the degree of MCP methylation tracks the attractant concentration, but after a short delay. This allows each cell to "calculate" the first derivative of the attractant concentration, and modify its behaviour appropriately. The negative feedback methylation system greatly increases the dynamic range of the receptor proteins, and also selectively amplifies the vital first derivative information that bacteria need for survival.

Key References: bacterial chemotaxis

• Wadhams & Armitage JP (2004) bacterial chemotaxis

• Baker et al (2006) bacterial signal transduction

• Rao et al (2008) adaptation in B. subtilis

• Alexander et al (2010) coupling proteins

• Soujik & Armitage (2010) spatial organisation

Despite their relative simplicity, bacterial chemosensors are typical "external facing" sensors. They are fast, sensitive (protein kinase amplifier) and highly selective (partly through the use of periplasmic binding proteins), they adapt to ongoing stimuli (through methylation), they report changes not the steady state, and they have an "on/off" digital output: tumble or swim. Similar selection presures may generate similar adaptations throughout the living world.

Traps for the unwary: Bacteria are full of variety, and collectively respond to a vast range of compounds. Some swim towards oxygen, some swim away from it. In addition to the periplasmic binding proteins, there are inputs from the phosphotransferase system responsible for sugar uptake, and from cytosolic receptors as well as those in the periplasmic space. Parts of the signalling system are the opposite way round in Gram-negative E. coli and Gram-positive B. subtilis however the overall response is similar. There are other types of bacterial motility in addition to rotating flagellae. Some of this is better covered in the review by Szurmant & Ordal (2004) which has a very helpful table of protein components.

Self-assessment test

This is based on the article by Wadhams & Armitage (2004) Nature Reviews Molecular Cell Biology 5, 1024-1037. This somewhat prolix example is a little repetitious and intended for formative use.

Reprinted by permission from Macmillan Publishers Ltd: Wadhams GH & Armitage JP (2004) "Making sense of it all: bacterial chemotaxis" Nature Reviews Molecular Cell Biology 5, 1024-1037, fig. 2 copyright 2004. License number 2327540163221

Eukaryotic sensory pathways commonly rely on serine, threonine or tyrosine protein kinases, whereas prokaryotes often use histidine–aspartate phosphorelay (HAP) systems. HAP systems have at least two components — a dimeric histidine protein kinase (HPK) and one or more response regulators (RR). CheA is a dimeric HPK that interacts with transmembrane receptors. The kinase domain of one monomer phosphorylates a (1) arginine aspartate cysteine glutamate histidine lysine serine threonine tyrosine residue in the other. The phosphoryl group is then transferred to a conserved (2) arginine aspartate cysteine glutamate histidine lysine serine threonine tyrosine residue of the relevant RR, activating the output domain of the RR. Two response regulators CheY and CheB compete for binding to CheA. E. coli move by rotating five to eight helical flagella anticlockwise, causing them to wrap together into a bundle that propels the cell forwards. Temporarily rotating some flagellae clockwise disrupts this bundle, causing the cell to tumble. When the motors resume anticlockwise rotation, the cell has reorientated and swims off in a new direction. In homogeneous environments, bacteria (3) remain stationary tumble ca. 10 times per second tumble ca. once per second tumble ca. once per ten seconds tumble ca. once per minute cease tumbling producing random motion. In non-homogeneous environments, variations in the intervals between tumbling bias the overall motion towards regions containing higher attractant concentrations, or lower concentrations of toxic chemicals. Bacteria are too (4) permeable impermeable mobile slow symmetric irregular large small round long to sense a spatial concentration gradient along their length and therefore use temporal sensing to monitor the concentration at more widely separated points. E. coli can detect transient changes in ligand concentration despite long-term variations in background concentration spanning five orders of magnitude. Chemotactic signals are detected by four dedicated transmembrane chemoreceptors: Tsr, Tar, Trg and Tap. These methyl-accepting chemotaxis proteins (MCPs) protrude through the inner membrane into the periplasmic space. MCPs bind some ligands directly, but respond to others with the assistance of periplasmic binding proteins. An adaptor protein, (5) CheA CheB CheB-P CheR CheW CheY CheY-P CheZ MCP PBP helps to link the MCPs to the cytoplasmic HPK, CheA. A continuously active methyltransferase enzyme (6) CheA CheB CheB-P CheR CheW CheY CheY-P CheZ MCP PBP preferentially methylates those MCPs which have bound attractants, but ignores those which have bound repellants. (7) CheA CheB CheB-P CheR CheW CheY CheY-P CheZ MCP PBP removes these methyl groups. This ultimately causes the average methylation level to track the net attractant / repellant balance, after a slight delay. Decreased concentrations of attractants result in decreased occupancy of MCPs, which stimulates CheA trans-autophosphorylation. This increases the concentration of (8) CheA CheB CheB-P CheR CheW CheY CheY-P CheZ MCP PBP which binds to the flagellar motor, causing a switch to clockwise rotation. This results in cell tumbling and direction change. A phosphatase (9) CheA CheB CheB-P CheR CheW CheY CheY-P CheZ MCP PBP terminates this process. CheB is also phosphorylated by (10) CheA CheB CheB-P CheR CheW CheY CheY-P CheZ MCP PBP and results in an increased methylesterase activity and demethylation of the MCPs. Demethylated MCPs have a reduced ability to induce CheA autophosphorylation (even in the presence of a low concentration of attractant) so the rate of CheA autophosphorylation and therefore the rate of direction changing returns to the pre-stimulus level. Adaptation is complete and the system is ready to sense further changes in ligand binding. Increased concentrations of attractant inhibit the autophosphorylation of CheA, which reduces the concentration of (11) CheA CheB CheB-P CheR CheW CheY CheY-P CheZ MCP PBP and therefore reduces the frequency of motor switching. This causes bacteria to swim for longer in the current desirable direction. CheB phosphorylation and methylesterase activity is also reduced, allowing (12) CheA CheB CheB-P CheR CheW CheY CheY-P CheZ MCP PBP to re-methylate the MCPs. Methylated MCPs stimulate CheA autophosphorylation, even in the continued presence of a chemoattractant, so CheA autophosphorylation returns to the pre-stimulus level and the bacterium to a normal frequency of direction changing. The MCP signalling domain contains two adaptation regions, each with four to six glutamate residues that can be reversibly methylated. Some of these glutamates are actually encoded as glutamines, which mimic methylated glutamates and probably ensure that newly translated MCPs are inserted into the membrane in a neutral signalling state. CheB is a dual-function enzyme, which can deamidate as well as demethylate MCPs. Deamidation of the glutamine residues to glutamates exposes new targets for methylation by CheR and, therefore, for adaptation.   feedback:  marks only error list commentary please remember to re-submit if you change the feedback setting

Click here to see the complete bacterial motility reference list.

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Lecture two: Primary cilia, GPCRs, GRKs and TRP proteins

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Primary Cilia

Many, perhaps most, animal cells possess a single non-motile "9 + 0" primary cilium, which arises from the "mother" (i.e the oldest) centriole close to the plasmalemma. Centrioles play key roles in animal cell division and are closely related to the basal bodies which organise the more common motile "9 + 2" cilia. Centrioles and basal bodies both contain a ring of 9 triplet microtubules, in contrast to the ring of 9 doublet microtubules found in the cilia themselves. [Cilia are a feature of animal cells and protozoa. Higher plants do not normally have centrioles or cilia, but may have ciliated sperm.]

The primary cilium appears first after cell division, and the much more numerous motile cilia in ciliated epithelia are apparently derived from the primary cilium by multiplication of the basal body. For many years primary cilia were regarded as vestigial structures, until they were discovered to play key roles in sensory transduction. Animal cilia are sometimes called flagella, but this term is now deprecated because of potential confusion with bacterial flagella which have a completely different structure. Distinguish also between centrioles, centrosomes and centromeres!

Many animal sensory transducers are derived from modified cilia. This is true for smell, vision, hearing and fluid flow. New functions are still being added to this list. With hindsight, it is hardly surprising that biosensors should be located on a cellular projection where they are better exposed to the environment. The primary cilium is increasingly referred to as the 'antenna' of the cell.

There is a good open access review: Singla & Reiter (2006) The Primary Cilium as the Cell's Antenna: Signaling at a Sensory Organelle. Science 313(5787), 629 - 633.

There are 10 - 30 olfactory cilia on each olfactory sensory neurone (OSN) and each cilium has a "9 + 2" axoneme with doublet microtubules in the short proximal segment near the basal body, rather than the "9 + 0" organisation in primary cilia. However, olfactory cilia are non-motile in most species, and have a long, thin distal segment containing 1 - 4 singlet microtubules. The distal segment carries most of the olfactory receptors. Unlike most nerve cells, OSNs have a relatively short life and are replenished from a stem cell population. The olfactory cilia are formed by repeated duplication of centrioles, followed by migration of the centrioles to the dendritic knob, where they are transformed into basal bodies. A single primary cilium appears first, before the remainder of the olfactory cilia are formed.

Vertebrate photoreceptors are derived from single, hugely modified primary cilium. Each of the sensory hair cells in the mammalian inner ear bears a single "kinocilium". This is a primary cilium that organises the stereocilia (microvilli) where vertebrate auditory transduction takes place. Defects in ciliogenesis can therefore have catastrophic "pleiotropic" effects on sensory development, and severe disabilities can result affecting several sensory modes.

Cilia form a distinct cellular compartment. Although there is no internal membrane bounding the base of each cilium, specialised proteins accumulate near the basal body and effectively close off the interior of the cilium from the remainder of the cell. Cilia grow by the addition of new subunits to the distal tip. Diffusion is difficult along these long, narrow organelles, and a specialised Intraflagellar Transport System (IFT) based on type 2 kinesins is used to specifically deliver particular proteins to the tip. A retrograde transport system based on cytoplasmic dynein returns damaged or surplus proteins to the base for recycling.

There is a recent mini-review on IFT: Scholey & Anderson (2006) Intraflagellar transport and Cilium-Based Signaling. Cell 125, 439-442.

There is collection of 13 essays on cilia, edited by Yoder (2008) Ciliary Function in Mammalian Development which is volume 85 in the series Current Topics in Developmental Biology. This book is mostly about the molecular biology of cilia rather than the details of mammalian development, and is highly recommended. In mammals (but not, apparently, in arthropods) primary cilia are involved in both hedgehog and wnt signalling, and help to establish the orientation of cell division. This is crucial for the correct differentiation of complex 3-D structures, such as kidney tubules, bones & teeth, olfactory epithelia, retina and cochlea.

Kidney

H&E-stained medullary ray from human kidney, courtesy of Dr. Lutz Slomianka, Zürich. Each human kidney contains about 1 million nephrons, illustrated in the cartoon below. Most of the water and solutes that are filtered in the glomerulus are resorbed in the proximal and distal convoluted tubules, and only a small proportion reaches the collecting duct. There is a large osmotic gradient from the outside of each kidney towards the middle. This gradient is produced by active sodium export from the tubule lumen to the interstitial space in the thick ascending limb of the loop of Henle, in conjunction with the passive water permeability of the descending limb and the counter-current fluid flows within the tubules and the capillaries. The osmotic gradient is exploited to concentrate the urine in the collecting ducts and to control its final osmolarity.

Cell turnover healthy adult kidney is slow, but increases greatly following injury or disease. Progenitor cells may be derived from both kidney and bone marrow. Embryonic differentiation and subsequent repair both involve cell migration and both require urine flow. Human nephrons are typically about 3cm long, but only 20 µm internal diameter, and it is clear that the cells require some signals to correctly orient themselves in relation to their neighbours.

Polycystic kidney diseases: (PKD) Many people develop a few isolated renal cysts in later life. When there are only one or two of these fluid-filled chambers they are often asymptomatic. Polycystic kidneys gradually become full of cysts, which compromise renal function. PKDs are serious, life threatening conditions, which often require dialysis or a kidney transplant. Various types of cystic kidney disease are outlined in the table below:

Polycystins 1 and 2 are associated in the ciliary membrane. The function of polycystin-1 is only partly understood, but polycystin-2 is an ion channel that is also known as TRPP2. It belongs to the transient receptor potential (TRP) protein family [discussed below] whose numerous members contribute to a wide range of sensory transducers. Polycystin-2 is also indirectly linked to fibrocystin, through their mutual binding to the KIF3B motor subunit of kinesin-2.

Primary cilia appear to sense fluid flow by passive bending, leading to Ca⁺⁺ entry via polycystin-2. Similar fluid sensing (or mechano-sensing) mechanisms seem to operate in kidney tubules, liver bile ducts, pancreatic ducts, bones and teeth.

Downstream signalling is thought to involve various routes. High internal Ca⁺⁺ is associated with the retention of P100 and stat-6 within the cilia, and the movement of inversin to the cytosol, where it targets the Wnt pathway protein dishevelled for proteasomal degredation. Fibrocystin is cleaved in a calcium-dependent manner, and its C-terminal fragment moves into the nucleus.

Lack of flow, and reduced Ca⁺⁺ leads to proteolytic cleavage of polycystin-1 and the translocation of the polycystin tail, P100 and stat-6 to the nucleus, where they modulate transcription.

Loss of cilial function through a wide variety of different mechanisms leads to inhibition of apoptosis, and the uncontrolled proliferation of kidney tubule cells. The orientation of cell division is incorrectly linked to tubule geometry, ultimately leading to the formation of cysts. This process may involve the serine / threonine kinase mTOR (mammalian target of rapamycin) which modulates ribosomal function and controls entry into the cell cycle. Preliminary results suggest that the immunosuppressant rapamycin, and the cyclin-dependent kinase inhibitor roscovitine may both be directly useful in the treatment of polycystic disease.

Mutations affecting ciliogenesis have pleiotropic effects on sensory transduction. For example, Bardet-Biedl syndrome is primarily associated with polycystic kidney disease due to loss of tubular flow sensing, but among a host of other symptoms it may also be associated with loss of smell, retinal degeneration and deafness. At least twelve different genes may contribute to this disease, but all of them are involved in ciliogenesis and intraflagellar transport. Several homologues have been identified in C. elegans and Chlamydomonas which are also involved in ciliogenesis. It is possible to produce mutant Drosophila lacking centrioles and cilia, which (amazingly) complete a near-normal development although, lacking most sense organs, they die shortly after metamorphosis.

Bone

Primary cilia are also believed to play a major role in shaping hard tissues such as bones and teeth. Please see the lecture slides for details of bone development and anatomical structure. Volume 291, issue 9 of the Anatomical Record has a series of papers detailing recent research on bone.

Unstained microscope image of compact bone, courtesy of Dr. Lutz Slomianka, Zürich. This type of bone is found on the outside of the long bones. Note the Haversian canal in the centre of the image, which contains blood vessels. The black osteocytes are emebedded in lacunae which are connected by the canaliculae (thin black lines).

Primary cilia have major sensory roles in bone and cartilage, where they are responsible for maintaining the shape and strength of the skeleton and connecting ligaments. Bone is subject to continuous remodelling throughout life, destruction and dissolution wrought by osteoclasts is compensated by continuous deposition of new bone by osteoblasts. Bone flexes under load, causing fluid to move through the internal canalicular network. This bends the primary cilia protruding into the canals, and initiates calcium-based signalling which ultimately maintains the correct shape and mineral density.

The September 2008 issue of the Anatomical Record has several papers on this important topic. See also:

Whitfield (2008) The solitary (primary) cilium – A mechanosensory toggle switch in bone and cartilage cells. Cellular Signalling 20(6), 1019-1024.

The best academic website on classical bone histology is "Blue Histology" at the University of Western Australia with a mirror site at University College, Cork. Follow the links to bone dynamics and also to their large images section.

Key References: primary cilia

• Menezes & Onuchic (2006) Polycystic kidney disease (picture).

• Marshall & Nonaka (2006) Tuning in to the Cell's Antenna .

• Bandano et al (2006) Ciliopathies.

• Singla & Reiter (2006) The Primary Cilium as the Cell’s Antenna.

• Simons & Walz (2006) Polycystic kidney disease.

• Hu et al (2006) TRPP function.

• Giamarchi et al (2006) TRPP function.

Click here to see the complete primary cilia reference list.

Ionotropic and metabotropic signalling mechanisms

Ionotropic signalling: The stimulus directly modifies an ion channel conductance in the receptor cell. Well known examples include nicotinic acetylcholine receptors, and hearing transduction. Ionotropic signalling is fastest because there are no intermediate stages, however there is less opportunity for modulation and filtering within the transducer itself.

Metabotropic singalling: The stimulus generates some chemical intermediate which must be further metabolised in order to change an ion channel conductance within the receptor cell. Well known examples include catecholamine β receptors and visual transduction pathways, both of which involve various types of G-protein coupled receptors. Metabotropic signalling is generally slower than ionotropic signalling, but there is more opportunity for modulation and filtering within the transducing cell.

G-protein coupled receptors GPCRs

Over 800 GPCRs have been identified in the human genome, and it is no surprise that several are involved in sensory transduction. GPCRs play major roles in taste, smell and vision. The classical signalling pathway involves a seven-transmembrane helix receptor linked via a heterotrimeric G-protein to a membrane-bound signaling enzyme, such as phospholipase C (taste, insect vision) , adenyl cyclase (smell) or phosphodiesterase (mammalian vision).

GPCR kinases (GRKs) and Arrestins

GPCRs trigger potent signaling cascades, which are required for fast and effective responses to important physiological stimuli. It is, however, vital for all organisms to terminate these responses quickly, and to adapt to ongoing stimuli for maximum biological effectiveness. It is difficult to pass on one's genes while existing in a permanent state of alarm.

A widely used mechanism is to phosphorylate the activated receptor using a variety of GPCR kinases (GRKs) after which an arrestin protein can bind and modify the signaling response. In addition to terminating the first response to a new stimulus, it is also possible to generate a different response to ongoing stimuli (such as receptor internalisation and down-regulation) that supersedes the initial reaction.

GRK mechanisms are important for visual adaptation, and for smell, and these are discussed in greater detail below. There is a special section on GRKs and Arrestins in volume 69 of the Annual Review of Physiology (2007) which is highly recommended for an overview of this important field.

Patch clamping

This powerful technique allows measurements on a single ion channels embedded in a patch of membrane. It has been hugely informative and the inventors Erwin Neher and Bert Sakmann shared the Nobel prize in 1991.

This is an important technique and all students should know about it, not just for this course. The best textbook account is in Boron & Boulpaep, but there is reasonable coverage in Stryer and also in Lodish. The essence of the technique is a small patch of excised membrane containing only one or two active ion channels stuck over the end of a micropipette. Depending on the experimental technique the patch may be either inside out or right way round, allowing ions and modulators to be applied to either side of the membrane. The recording equipment allows the experimeter to impose a fixed or time-varying potential across the membrane, while measuring the resulting current flow. This reveals the probability that the channel will be in the open state, and time course for some of the slower changes.

It has been particularly informative to express the genes for ion channel proteins in Xenopus oocytes, whose plasmalemma normally contains very few channels. The newly synthesised proteins are correctly inserted into the cell membrane, where they can be studied in the absence of interfering activities.

Transient receptor potential (TRP) channels

These were originally discovered in a Drosophila mutant that showed only a transient response to continuous illumination. They are among the most widely distributed receptor systems and numerous examples have been discovered in a wide range of species.

Recent review: Venkatachalam & Montell (2007) TRP Channels. Ann. Rev. Biochemistry 76, 387-417.

Key References: introduction to TRP channels

• Jordt SE et al (2003) introduction to TRP receptors

• Voets et al (2004) or Brauchi et al (2004) advanced work on heat and cold

• Voets et al (2005) Sensing with TRP channels

• Huang (2004) an overview of the entire TRP superfamily!

• Fleig & Penner (2004) review of the TRPM subfamily

• van der Stelt & Di Marzo (2004) endovanilloids

• Nilius et al (2004) gating diversity of TRPV4

• Liedtke & Friedman (2003) TRPV4 in osmoregulation

• Arniges et al (2004) defective osmoregulation in cystic fibrosis

• Tominaga & Caterina (2004) thermosensation and pain

• Lewin & Moshourab (2004) mechanosensation and pain

• Cervero & Laird (2004) visceral pain

The Clapham lab website has tables summarising the properties of the major TRP channels. The best recent TRP review is Voets' article in Nature Chemical Biology, but in October 2005 [vol. 451(1)] there was a whole issue of Pflugers Archive (European Journal of Physiology) devoted to numerous aspects of TRP channels, which includes a contribution from Professor Beech.

Click here to see the introductory TRP channel reference list.

TRP channels involved in metazoan sensory transduction

The key sensory channels are highlighted in red. Non-sensory channels are included for completeness.

Download this table in printable form.

Summary

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Lecture three: taste and smell

Mucosal chemosensors (taste, gut wall sensors, smell). Anatomy, evolution and embryology of taste and smell. Taste buds. Transducers for sweet, bitter, salty, sour and umami. GPCRs and ion channels. Gustducin. Other chemoreceptors along the GI tract. Olfactory receptor neurones. Glomeruli. Olfactory receptor families 1 and 2. Control of gene expression. Human / mouse comparisons. Vomeronasal organs. Sexual selection and MHC classes. Sperm chemoreceptors.

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Taste

H&E stained circumvallate taste bud, courtesy of Dr. Lutz Slomianka, Zürich. These are the largest taste organs, which form a readily visible line of pimples towards the back of the tougue. Hundreds of individual taste buds sample material in the deep cleft that surrounds each structure.

Mature taste bud cells all have prominent microvilli. They are continuously renewed from a local population of stem cells and their half-life is about ten days. Type I "dark" cells are glial (supporting) cells, but also contribute to salty (chloride) tastes. The full salt flavour may also require sodium channels. Sub-populations of type II cells respond to sweet, bitter, umami (glutamate) and fats. They release ATP which stimulates purinergic receptors on type III cells and also on sensory neurones. Type III cells signal "sour" after intracellular acidification. Only type III cells make synaptic connections, where they release serotonin.

The sensory nerves are "labelled lines" which always convey the same taste sensation, regardless of the source of the stimulation. Nerve "cross over" experiments have shown that stem cell differentiation into specific taste transducer cells is an inherent property of the epithelium, and is not controlled by the nerves. We do not know how the differentiating taste bud cells recognise their appropriate nerve connections, nor how their relative numbers are controlled. The same issues also arise with olfactory receptor cells, which are maintained in a similar manner.

The fundamental sensing mechanism for sweet, bitter and umami involves different permutations of GPCR receptors linked through phospholipase C β2 which hydrolyses phosphatidyl inositol to yield IP3 and diacylglycerol. Fat sensing uses different receptors but connects to the same signalling system. The IP3 releases internal Ca⁺⁺ stores which open TRPM5 channels, depolarising the cells and stimulating neurotransmitter and neuropeptide release. Neuroendocrine cells similar to taste buds are present throughout the GI tract, where they regulate the later stages of the digestive process as well as food intake through the mouth.

Rozengurt & Sternini (2007) Taste receptor signaling in the mammalian gut. Current Opinion in Pharmacology 7(6), 557-562.

Huang et al (2008) Presynaptic (Type III) cells in mouse taste buds sense sour (acid) taste. J. Physiol. 586(12), 2903-2912. (sour taste)

Matsumura et al (2009) Colocalization of GPR120 with phospholipase-Cβ2 and α-gustducin in the taste bud cells in mice. Neuroscience Letters 450(2), 186-190. (fat receptors)

Ishimaru (2009) Molecular mechanisms of taste transduction in vertebrates. Odontology 97, 1–7. (recent review)

• Cummings & Overduin (2007) gastrointestinal regulation of food intake

• Chandrashekar et al (2006) receptors and cells for mammalian taste.

• There is a group of excellent papers in Nature 16 November 2006.

• Scott (2004) brief introduction to taste receptor genes

• Zhang et al (2003) deciphering the sweet, bitter and umami pathways

• He et al (2004) and Ozeck et al (2004) G protein signalling

• Liu & Liman (2003) and Prawitt et al (2003) TRPM5 channels and calcium

• von Buchholtz et al (2004) regulator of G protein signalling

• Lyall et al (2004) salt tastes; Ugawa et al (2004) sour tastes

• Hiroi et al (2004); Thorne et al (2004); Wang et al (2004) taste in Drosophila

• Wu et al (2002) and Benson et al (2002) gut wall receptors and CCK release

• Mombaerts (2004 a) brief account of Nobel prize for Buck & Axel

• Mombaerts (2004 b) comprehensive review of olfaction and taste receptors

• Kaneko et al (2004) chloride ions in olfactory neurones

• Matthews & Reisert (2003) calcium and olfactory adaptation ***

• Mamman et al (2004) hypocalcin and olfactory adaptation

• Hallem & Carlson (2004), Melkman & Sengupta (2004) olfaction in Drosophila and Caenorhabditis

• Hinterwirth et al (2004) cockroaches can calculate first derivatives!

• Strotman et al (2004), Feinstein & Mombaerts (2004), Feinstein et al (2004) axonal guidance

• Leinders-Zufall et al (2004) vomeronasal organ

• Fukuda et al (2004), Spehr et al (2004), Ziegler et al (2002) MHC and ORs in sperm

Traps for the unwary: like most other biological transducers, taste adapts to ongoing stimuli, as cooks have realised for thousands of years. Unfortunately, except for some limited work on sour taste receptors, we have little idea of how taste adaptation is achieved. Adaptation in olfactory sensory neurons certainly involves calcium ions, although other mechanisms may also be operational.

Smell

Each olfactory sensory neuron expresses only one olfactory receptor (OR) on its sensory cilia. Mice and dogs have about 1000 functional ORs but most human ORs are pseudogenes. It is not yet clear how only one gene is selected per cell, or how each cell finds its matching glomerulus in the olfactory bulb. The same unique protein is expressed on the axonal process and somehow enables the axon to converge with other similar axons onto their common glomerulus in the olfactory bulb. These processes must be repeated throughout life, because olfactory receptor cells survive for only 2 weeks and are continuously renewed from a population of stem cells.

Ofactory adaptation involves the negative feedback systems shown in the diagram above, and also may involve the temporary internalisation of receptors into a storage compartment.

Olfactory transduction is a "many to many" process. Each olfactory receptor cell (ORC) expresses only 1 of 1000 possible receptor molecules. There are many similar cells in the olfactory epithelium, but all the ORCs that express the same receptor converge on one or two matching glomeruli within the olfactory bulb. We do not properly understand how they all find their correct target. The olfactory bulb is an extension of the brain that lies immediately behind the bony lining of the nasal cavity.

Each ORC responds to a range of similar odorants, but responds to some much more strongly than others. Each odorant may trigger more than one type of ORC. Within the olfactory bulb there are inhibitory and excitatory pathways between the various glomeruli, which are homologous to similar pathways within the retina. In essence these circuits carry out contrast enhancement, so the overall pattern of signals from the glomeruli to the rest of the brain reflects the precise odour being sensed.

Similar synaptic organisation in the olfactory bulb and retina

Adapted from The synaptic organisation of the brain. G.M. Shepherd (OUP 2004) p35.

There is a general similarity between the neuronal organisation in the olfactory glomeruli and in the retina. The correspondence is not exact, because they have different tasks to perform. In the eye, spatial correlations are all-important, but in the nose temporal changes carry more information. A dog following a scent swings its nose from side to side, thereby generating d(smell)/dt and d²(smell)/dt²

This time derivative data is vital for following the trail. Insects require similar information to correctly follow a scent plume leading to their mate or their next meal. The physical position of each glomerulus within the mammalian olfactory bulb is inherited, tightly controlled and conserved across species, but there is no obvious pattern to it, and glomeruli that respond to very different stimuli may be immediately adjacent to one another.

Soucy et al (2009) Precision and diversity in an odor map on the olfactory bulb. Nature Neuroscience 12(2), 210-220. [See also News & Views.]

Kleene (2008) The Electrochemical Basis of Odor Transduction in Vertebrate Olfactory Cilia. Chemical Senses 33(9), 839-859.

Imaia & Sakano (2008) Odorant receptor-mediated signaling in the mouse. Current Opinion in Neurobiology 18(3), 251-260.

Song et al (2008) Olfactory CNG Channel Desensitization by Ca2+/CaM via the B1b Subunit Affects Response Termination but Not Sensitivity to Recurring Stimulation. Neuron 58(3), 374-386.

Ma (2007) Encoding Olfactory Signals via Multiple Chemosensory Systems. Critical Reviews in Biochemistry and Molecular Biology 42(6), 463 - 480.

Grosmaitre et al (2007) Dual functions of mammalian olfactory sensory neurons as odor detectors and mechanical sensors. Nature Neuroscience 10(3), 348-354.

Mashukova et al (2006) β-Arrestin2-Mediated Internalization of Mammalian Odorant Receptors. J Neuroscience 26(39), 9902–9912.

Brady et al (2006) Interplay between PIP3 and calmodulin regulation of olfactory cyclic nucleotide-gated channels. PNAS 103(42), 15635–15640.

The vomeronasal organ is an accessory olfactory area that specialises in the detection of sexual smells and social status. Its function seems to be linked to the MHC system, with the result that many mammals prefer sexual partners that will optimise the immune capabilities of their offspring. It is disputed whether a similar system operates in humans.

MHC proteins and a subset of ORs are also expressed in sperm, where they may participate in sperm chemotaxis, and ensure that eggs are more likely to be fertilised by an immunologically compatible sperm.

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Lecture four: vision

Vision. Anatomy of the eye and brain, evolution and embryology. Histology and cell biology of the retinal photoreceptors and the retinal pigment epithelium. Vertebrate visual transduction pathway: rhodopsin, transducin, cGMP phosphodiesterase, cGMP-gated sodium channels, membrane potential. Time course for light adaptation. Rhodopsin kinase. Arrestin. Colour vision. Invertebrate light receptors, visual transduction and adaptation. Repair and maintenance of the visual equipment. Kinesins. Usher syndrome. Retinitis pigmentosa.

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All species

rhodopsin - 7 transmembrane receptor containing 11-cis-retinal, isomerised to meta-rhodopsin II containing trans-retinal by light absorption.

Rhodopsin X-ray structure

The X-ray structure is known at 2.8 Angstrom resolution. Click the link to display rhodopsin and ligands using Chime software.

Basic visual transduction system in mammals

The best vision website is Webvision at the University of Utah, which has stunning graphics, time lapse photography, microscopy and animations. It is a shame that we do not have sufficient time to explore this resource in greater detail.

The retina is a complex multi-layer structure which processes the raw photoreceptor output and principally reports changes in image contrast to the brain. See Field & Chichilnisky (2007) Information Processing in the Primate Retina: Circuitry and Coding. Annu. Rev. Neurosci. 30, 1–30. Fundamentally, the retina analyses the image for dark spots surrounded by light areas, and light spots surrounded by dark areas. If adjacent light and dark areas can be fused into lines these have potential survival value, and their orientation and location are reported to the brain. Large areas of constant colour and illumination have little biological significance and are largely ignored by the visual circuits. Most cells in the retina respond to illumination with graded changes in membrane potential, but the ganglion cells fire action potentials and their axons constitute the optic nerve. The photoreceptors are at the back of the retina, embedded in the retinal pigment epithelium, or RPE. The RPE is much more than a black anti-reflection coating, and plays a major role in photoreceptor physiology.

In life, most images on the retina are in constant motion. Gaze moves rapidly in a series of saccades from one point of interest to the next, and in addition, the brainstem generates an occular microtremor at about 80Hz. This tremor has been used to estimate the depth of surgical anaesthesia and to diagnose brainstem death. Images that are artificially stabilised on the retina using an optical feedback system gradually fade away, and even under normal circumstances the changes associated with image movements are believed to assist visual processing: Rucci & Desbordes (2003) Contributions of fixational eye movements to the discrimination of briefly presented stimuli. Journal of Vision 3(11), 852-864.

There are two classes of photoreceptors with a slightly different constructions. The rod cells are longer and provide monochromatic vision in dim light, in contrast to the fatter cones which come in red, green and blue flavours and provide colour vision in bright light. All photorecepors use rhodopsin and the colour specialisation arises from differences in the protein sequence. Photoreceptor cells survive throughout life, but the photosensitive discs in the outer segment are continually renewed. Kinesin-2 drags new disc materials along the short primary cilium to the base of the outer segment. Over the coure of the next month each disc gradually migrates outwards along the outer segment, until eventually it is shed from the tip and phagocytosed by the RPE.

In mammals the RPE is also responsible for recycling trans-retinal back to cis-retinal and returning it to the photoreceptors. The active chromophore 11-cis-retinal is an aldehyde that forms a Schiff base with lysine 296 in opsin. Light absorption converts it to all trans retinal, which dissociates from the protein within seconds and is reduced within the receptor cell to all trans retinol, or vitamin A. The vitamin A is taken up by the RPE and esterified with palmitate taken from membrane phospholipids. An isomerohydrolase then converts the trans retinol to 11-cis-retinol, using the energy released by ester hydrolysis to drive the thermodynamically unfavourable isomerisation reaction. The 11-cis-retinol is oxidised to 11-cis-retinal within the RPE before it is returned to the photoreceptor cells and recombined with opsin.

Visual transduction in mammals

1. In the dark, there is a high internal concentration of cyclic-GMP in the rod outer segments. cGMP keeps a ligand-gated TRP channel open in the plasmalemma, leading to rapid entry of sodium ions which partially depolarises the cell [-30mV]. The synaptic body continuously secretes glutamate, which is an inhibitory neurotransmitter.

2. Rhodopsin is a 7-transmembrane helix integral membrane protein plugged through the disc membranes. The retinal chromophore is buried deep in the lipid bilayer. Key interactions are all on the cytosolic side of the disc membrane.

3. Photoexcited rhodopsin binds to a G-protein transducin, and exchanges GTP for GDP thereby activating transducin. This process is typically repeated several hundred times, hugely amplifying the original signal.

4. The T_α subunits dissociate from the G-protein and activate a cyclic GMP phosphodiesterase associated with the disc membrane. The phosphodiesterase provides a second stage of signal amplification.

5. The concentration of cyclic-GMP falls within a fraction of a second, closing the sodium channels. c-GMP binding is highly cooperative process, with a Hill coefficient of 3.

6. The rod outer membrane hyperpolarises [-70mV], and the internal calcium concentration falls.

7. The synaptic body stops secreting inhibitory neurotransmitter, thereby exciting bipolar cells within the retina.

8. T_α subunits bound to phosphodiesterase hydrolyse GTP, thereby terminating their own activity.

9. Rhodopsin kinase phosphorylates photoactivated rhodopsin on the cytosolic surface of the discs.

10. Arrestin binds to phosporylated rhodopsin and blocks further transducin binding.

11. The fall in calcium concentration stimulates rhodopsin kinase, via the protein recoverin, as part of the adaptation process.

12. The fall in calcium concentration stimulates guanyl cyclase, restoring the cGMP concentration as part of the adaptation process.

13. Transducin, arrestin and recoverin are moved between the rod inner and outer segments as part of the adaptation process.

Adaptation

Visual adaptation has several components, which differ in speed and dynamic range. At the most basic level, photodissociation of activated rhodopsin bleaches the protein and renders it temporarily unavailable for further transduction events. Reactivation in mammals depends on retinal recycling within the RPE, which is relatively slow. The percentage of bleached rhodopsin in the photoreceptors rises as the light intensity increases, so there is less coloured rhodopsin available to absorb light. This leads to a fall in light sensitivity at high light intensities, and increases the dynamic range. In normal daylight, essentially all the highly sensitive rod photoreceptors are fully bleached, so the rods contribute relatively little to daytime vision.

Adaptive movement of proteins along the primary cilium - modified from Calvert et al (2006).

Compare and contrast visual transduction and adaptation in mammals and drosophila.

• Nayak et al (2007) Melanopsin

• Calvert et al (2006) Adaptation

• Fernald (2006) Evolution

• Palczewski (2006) Rhodopsin review

• Kremer et al (2006) Usher syndrome

• Hartong et al (2006) Retinitis pigmentosa

• Peirson & Foster (2006) melanopsin

• Burns & Arshavsky (2005) vertebrate visual transduction

• Arshavsky et al (2002) G proteins and phototransduction

• Fain et al (2001) adaptation in vertebrate photoreceptors

• Hardie & Raghu (2001) and/or Hardie (2001) transduction in Drosophila

• Delmas et al (2004) PLC signaling microdomains in Drosophila

• Arendt et al (2004), Nilsson (2004) and Triesman (2004) evolution of eyes

• Lee & Montell (2004) and/or Cronin et al (2004) subcellular translocation (preview article)

• Baker et el (2003) Scholey (2003) ciliary transport

• Snell et al (2004) cilia & flagella revealed

• Xue et al (2004) retinal recycling

• Liu et al (2003) retinitis pigmentosa (see OMIM for more examples)

• Wassle (2004) retinal processing

• Sakmar et al (2002), Filipek et al (2003) rhodopsin X-ray structure

Traps for the unwary: There is little doubt that the Drosophila visual transducers outperform the vertebrate system so far as light detection is concerned. Although both systems can detect single photons, insect detectors respond faster than rods and cones, have better signal to noise ratios and a greater dynamic range.

Perhaps when assessing phototransducer performance we are looking at the wrong thing. Vertebrates excel in image analysis. What matters to most animals are changes or differences in colour and light intensity, which signal threats, opportunities and mates. Constant signals have little biological interest. The vertebrate retina identifies and magnifies these differences and filters the most relevant information before transmitting it to the brain. In achieving this objective, the ability of the photoreceptors to adapt to differing light intensities is paramount for success.

Retinal connections

[Simplified diagram adapted from Dowling (1997) Encyclopedia of Human Biology, vol. 7 pp 571-587.]

Photoreceptors make a graded response to illumination. Rods and cones hyperpolarise when illuminated, and reduce their glutamate output. Bipolar cells also make graded responses, but may either depolarise or hyperpolarise depending on the local circuitry. Amacrine cells and horizontal cells compare and contrast signals from adjacent photoreceptors, looking for dots and edges, and it is only the ganglion cells that generate normal action potentials.

There is a major issue about eye evolution. Ciliary and rhabdomeric eyes appear "out of nowhere" in the fossil record about 543 million years ago, across a wide range of species, but the molecular data and especially the role of Pax6 in eye development suggest a common origin pre-dating bilaterian animals many millions of years earlier. The December 2006 issue of Arthropod Structure & Development (volume 35, issue 4 "Origin and Evolution of Arthropod Visual Systems") is largely devoted to this fascinating problem, and includes some stunning electron micrographs.

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Lecture five: hearing

Hearing. Anatomy of the ear and auditory nerve, evolution and embryology. Cochlea compartments: endolymph and perilymph. Organ of Corti, tectorial membrane, inner and outer hair cells. Stereocilia. Transduction mechanism. Adaptation motor. Spiral ganglion, afferent and efferent nerves. Outer hair cell motility. Frequency-selective amplification, attenuation and phase locked loops. Usher syndrome.

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Study the gross anatomy of the ear in a text book. The best diagrams are in Tortora & Grabowski, but Kandel is also good. This isn't an anatomy course, but you must understand how the various parts fit to together to make sense of their function.

Sound waves striking the external ear (pinna) are directed into the auditory canal, where they cause the eardrum to vibrate. These vibrations are transmitted through the air-filled middle ear via three small bones (malleus, incus and stapes) to the fluid-filled vestibule and cochlea which are part of the inner ear.

Each cochlea is roughly the size of your little finger nail, and has a spiral structure like a snail shell. It is divided internally into three compartments by the basilar membrane and by Reisner's membrane. The scala vestibuli communicates directly with the vestibule, and is also connected to the scala tympani via a small hole, the helicotrema at the apex of the cochlea. The scala media does not connect with either of the other two compartments, but is continuous with the space inside the semi-circular canals.

Perilymph is on the outside of the transducing equipment, in the scala vestibuli and the scala tympani. It has a high sodium content and is similar to cerebrospinal fluid. Endolymph is on the inside, in the scala media, and is in contact with the transducing hair cells (see below). Endolymph has a high potassium content (150mM) and is secreted by the stria vascularis. The scala media is 80 to 100mV positive with respect to the external perilymph. This endocochlear potential is essential for hearing transduction, and is generated by Kir4.1 potassium channels in the basal cells of the stria vascularis.

The transducers are hair cells,each of which bears a bundle of actin-based stereocilia (microvilli) on its exposed surface. A single primary cilium (kinocilium) also forms part of each bundle. This cilium is required for bundle assembly, but apparently plays no direct role in sensory transduction. This intricate and elaborate system apparently evolved from a flow sensor in a pre-cambrian filter feeding animal about 600 million years ago. This evolved further to make balance and acceleration measurements in primitive fish, and subsequently to transduce sound vibrations that are scarcely larger than atomic dimensions. Bending of the stereocilia opens ion channels in the cell membrane and initiates the transduction process.

In life the tectorial membrane is closely applied to the hair cell stereocilia, which tilt backwards and forwards as the membranes vibrate. The main detectors are the inner hair cells, which have a dense sensory innervation. Mechanically gated ion channels in the stereocilia open and close as the bundle rocks with each vibration. Until recently the vertebrate transduction channel was believed to be TRPA1 but this has been disproved by gene knockout experiments. The endocochlear potential drives potassium (and calcium) ions into the hair cells when the tip channels open, and allows these cells to track the precise waveform of the input signal in real time. Such speed is essential to accurately locate sound sources in a three-dimensional space.

There is an ancient sound amplification system that relies on active movements by the stereocilia to compensate for viscous damping within the passive transduction equipment. [Hudspeth (2008) Making an Effort to Listen: Mechanical Amplification in the Ear. Neuron 59(4), 530-545.] Such strategies have been used in regenerative radio receivers for almost a century, but the auditory equivalent presumably evolved about 500 million years ago in Cambrian times, since it is found throughout the vertebrate lineage and there is a similar system, based on primary cilia rather than microvilli, in insect chordotonal organs.

Drosophila chordotonal organs. Adapted from Bechstedt & Howard (2008) Hearing Mechanics: A Fly in Your Ear. Current Biology 18(18), R869-R870. See also Nadrowski et al (2008) Transducer-Based Force Generation Explains Active Process in Drosophila Hearing. Current Biology 18(18), 1365-1372.

Mathematical analysis shows that the coupled arrays of detectors found in the cochlea outperform their individual transducers by a considerable margin. [Dierkes et al (2008) Enhancement of sensitivity gain and frequency tuning by coupling of active hair bundles. PNAS 105(48), 18669-18674. The maths may be difficult to follow, in which case we recommend the "News & Views".]

Mammalian cochlea can amplify extremely faint sounds, and this process requires active movement by the outer hair cells, which have very few sensory fibres but a largely motor innervation coming from the brain. These anatomical features are not present in lower vertebrates, which rely only on active stereocilia. Sound production by the stereocilia and / or the outer hair cells is readily detectable as otoacoustic emissions. It may become pathological, leading to some forms of tinnitus. Individual hair cells and the basilar membrane are tuned to respond to specific frequencies, and this is achieved in part by differential mRNA splicing. High frequencies are detected near the base of the cochlea, and lower notes towards the apex.

There is a precise tonotopic mapping between the frequency selective regions of the cochlea, and the downstream processing within the hindbrain and the auditory cortex. These connections are made in the embryo before the auditory transduction mechanism has matured. It is now believed that a temporary supporting structure called Kölliker’s organ stimulates the immature hair cells via a purinergic pathway, causing them to fire in complex patterns that allow the corresponding neurones to make the correct connections. See Forsythe (2007) A fantasia on Kölliker’s organ Nature 450, 43-44.

Amplification and detection by the cochlea is frequency-selective and adjustable, so that faint sounds can be analysed while ignoring much louder noises at neighbouring frequencies. The detection system preserves the phase and intensity of the original noise, allowing the source to be located in space. The detection system adapts to varying sound intensities. Adaptation requires motor proteins. At least two separate processes are involved with very different response speeds.

There is an important review by Vollrath et al (2007) The Micromachinery of Mechanotransduction in Hair Cells. Ann. Rev. Neurosci. 30, 339-365. Unfortunately figure 1 from this review has the wrong orientation for lectures when downloaded, so I have reproduced it in the correct orientation below:

Students are strongly urged to read this review, BUT it makes no mention of important motor proteins, such as prestin, or the cochlear amplifier.

Fortunately, there is another review by Ashmore (2008) Cochlear Outer Hair Cell Motility Physiol Rev 88, 173-210 which deals with this aspect, so students should read both reviews to get the full picture. Prestin is a very unusual biological motor, that responds directly to membrane potential at very high speed. It seems to have evolved from an ion channel that has lost its channel functions. It does not require ATP hydolysis for motility and derives its energy directly from the transmembrane electric field. It is the biological equivalent to a piezo-electric transducer.

The adaptation motor is the class 1 myosin, Myo1C, which has a very different cross-bridge cycle and calcium sensitivity to the "conventional" class 2 myosin found in voluntary muscle. See Adamek et al (2008) Calcium sensitivity of the cross-bridge cycle of Myo1c, the adaptation motor in the inner ear. PNAS 105(15), 5710–5715. Calcium detaches Myo1C from the actin filaments. In 'resting' hair cells, with a low internal calcium, Myo1C complexes creep outwards along the actin filaments in the sterocilia, tensioning the tip links until these are just on the point of opening the transduction channels, resulting in a slow inward calcium leak. The system then remains in dynamic equilibrium, with motor slipping exactly balancing the motor tug. Louder noises fully open the channel, and the greatly increased calcium concentration detaches the myosin from the actin and greatly increases the rate of slipping. The adaptation motor slides back down the actin, slackening the tip links until calcium entry is restored to the resting level.

Several other myosins are involved in stereocilia assembly. [Manor & Kachar (2008) Dynamic length regulation of sensory cilia. Seminars in Cell & Developmental Biology 19, 502–510.] Hair cells are not renewed, and must be maintained throughout life. The graded lengths of individual stereocilia within the bundle are achieved by differential actin treadmilling, regulated by myosins Ia, Ic, IIIa, VI, VIIa and XVa. Loss of any of these "unconventional" myosin genes leads to non-syndromic deafness in animals and man.

There is an absolutely stunning website written by Mammano & Nobili which explores the anatomy and physiology of the mammalian cochlea in amazing detail. It is difficult to speak too highly of this site, which is full of brilliant anatomical drawings, scanning EM pictures, confocal images, video recordings and suberb computer animations. It takes several hours to read, but it is excellent throughout.

Other recent papers include:

Mio et al (2008) The Motor Protein Prestin Is a Bullet-shaped Molecule with Inner Cavities. J Biol Chem 283(2), 1137–1145.

Stauffer & Holt (2007) Sensory Transduction and Adaptation in Inner and Outer Hair Cells of the Mouse Auditory System J Neurophysiol 98, 3360-3369.

Grant & Fuchs (2007) Auditory transduction in the mouse Pflugers Arch - Eur J Physiol 454, 793–804.

The December 2006 issue of Journal of Physiology (volume 576, issue 1) has an excellent collection of papers on the cochlea.

• Reiners et al (2006) Usher syndrome

• Couloigner et al (2006) ion transport

• Hibino & Kurachi (2006) K+ circulation

• Wangeman (2006) endocochlear potential

• Fettiplace (2006) active hair cell movements

• Dallos et al (2006) prestin & cochlear amplifier

• Corey (2006) transduction channel

• Frolenkov (2006) electromotility

• Cooper & Guinan (2006) efferent control of basilar motion

• Moser (2006b) ribbon synapse

• Fritsch et al (2006) hair cell regeneration

• Clark (2006) cochlear implants

• Fettiplace & Hackney (2006) auditory hair cells

• Robles & Ruggero (2001) cochlea mechanics

• Marcus et al (2002) endocochlear potential

• Fettiplace & Ricci (2003) adaptation in hair cells

• Gillespie & Cyr (2004) myosin-1c is the adaptation motor

• Corey et al (2004) Ashmore (2004) TRPA1 is the transduction channel

• Fuchs et al (2003) afferent synapse

• Lioudyno et al (2005) cholinergic hair cell inhibition

• Santos-Sacchi (2003) outer hair cells Yale Ear Lab hair cell video

• Chan & Hudspeth (2005) cochlear amplifier

• Duncan & Fuchs (2003) differential splicing tunes cochlea

• Kennedy et al (2005) force generation by hair bundles

• Gopfert et al (2005) and Jarman (2002) Drosophila amplifiers and mechanotransducers

• Streit (2001) evolution of the inner ear

• Burighel et al (2003) ascidian hair cells

• Hawkins & Lovett (2004) hair cell development

• Belyantseva et al (2005) myosin XVa and whirlin

• Sziklai (2004) calcium in hair cells

• Kikkawa et al (2005) whirlin controls stereocilia length

• Buss et al (2004) myosin VI.   Search OMIM for myosin and deafness

• Kappler et al (2005) zebra fish myosin VI

• Adato et al (2005) Usher syndrome.   Search OMIM for Usher syndrome

Adaptation is once again the key to biological success. The cochlea is a frequency-selective amplifier, similar to a graphic equaliser on a hifi outfit, except that there are thousands of independent controls, each of which can be adjusted in real time to amplify only those frequencies currently of interest to the organism and to ignore everything else.

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Lecture six: mechanotransducers, pain, glucose and oxygen

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Mechanotransducers (touch, tendon organs, muscle spindles, blood pressure, osmotic pressure) and internal chemosensors (pH, carbon dioxide, oxygen). ENaC and TRP families. Internal sensors have smaller dynamic range, less adaptation than external sensors. Islet cells, hypothalamus, solitary tract, portal vein, carotid bodies.

Touch

The TRPC1 channel confers stretch sensitivity on many cell types. Normal touch sensitivity requires members of the degenerin / epithelial sodium channel family (Deg/ENaC). Mutations in these genes cause neurodegeneration, hence the name. They mediate touch sensitivity in C. elegans (O'Hagan et al, 2004) and are widely distributed in mammals. These pH- and amiloride-sensitive channels have a variety of alternative names, including ASIC and BNAC.

H&E-stained Pacinian corpuscles at the boundary between the dermis and hypodermis, courtesy of Dr. Lutz Slomianka, Zürich.

Golgi tendon organs measure tension, while muscle spindles signal rate of shortening as well as absolute length, but their receptors are not well characterised at a molecular level. Mechanical stretch has major effects on fibroblast and muscle growth, where uniaxial and multiaxial stretch have different receptor pathways (Hornberger et al, 2005). The high threshold mechanotransducer that responds to painful stimuli has not yet been identified (Hu et al, 2006) although there is no shortage of candidates. Mechanosensitivity is common, with many poorly characterised genes, so progress in this area has been relatively slow.

Proteases are released during inflammation, and protease-activated receptors (Grant et al, 2006) sensitise TRPV4 and are thought to be responsible for the pain and increased mechanical sensitivity associated with inflammation. TRPV4 is also involved in the baroreceptors that help to regulate blood pressure, and (with TRPV2) in cerebral osmotic pressure sensing (Liedtke, 2006) and vasopressin release.

Oxygen

Although it is essential for multicellular organisms, oxygen is an extremely reactive and potentially toxic gas. It oxidises sulphydryl groups and damages unsaturated lipids, generating free radicals which cause additional damage to proteins and nucleic acids. Regulatory mechanisms have evolved which keep tissue oxygen levels in the micromolar range, which is sufficient for mitochondrial respiration, while restricting non-enzymatic oxygen damage to sensitive molecules. Vertebrates have pre-capillary sphincters that regulate oxygen delivery to tissues. Similar systems are found in insect spiracles (Hetz & Bradley 2005, Burmester 2005) where oxygen is delivered in gaseous form.

Oxygen sensing is important for the regulation of breathing and cardiac output. A major sensor in humans is located in carotid bodies, but inumerable minor sensors are responsible for the local regulation of blood flow. Note that vascular regulation in the lung diverts blood away from underventilated regions, which is the opposite way round to regulation in peripheral tissues, where blood is diverted towards areas of oxygen need. Reports (Kemp, 2005) that hemoxygenase-2 (HO-2) is the oxygen sensor, and the second messenger was carbon monoxide cause great excitment, which has recently been tempered by a report (Otega-Saenz et al, 2006)that oxygen sensing remains intact in HO-2 knockout mice.

Many other systems have been proposed as cellular oxygen sensors, including succinate dehydrogenase and AMP-activated protein kinase (Evans, 2005). The September 2006 issue of Experimental Physiology (volume 91, issue 5) has a symposium on oxygen sensing.

• Hildebrandt F, Otto E (2005) primary cilia and diseases

• Ernstrom & Chalfie (2002) vast review on mechanotransduction genetics - good diagrams

• Pazour & Whitman (2003) and Snell et al (2004) minireviews on primary cilia

• Scholey (2003) intraflagellar transport

• Alieva & Vorobjev (2004) primary cilia disappear in cultured cells. serial EM pictures. membrane fusion

• Praetorius & Spring (2005) major review on primary cilia

• Zhang et al (2004) and Rogers et al (2004) kidney primary cilia, exocyst

• Delmas P (2005) polycystins and mechanotransduction

• Whitfield (2003) osteocyte primary cilia

• Whitfield (2004) neuronal primary cilia

• Magloire et al (2004) odontoblast primary cilia

• Jensen et al (2004) chondrocyte primary cilia

• Corey (2003) list of TRP mechanotransducer channels

• Ronan & Gillespie (2005) and Goodman et al (2004) brief reviews on mechanotransduction

• Syntichaki & Tavernakis (2004) vast review on mechanotransduction - good diagrams

• Zhang et al (2004) assembly of mechanical linkages in C. elegans

• Buttner-Ennever et al (2003) motor and sensory innervation in extra-ocular muscles

• Han et al (2004) mechanical stretch and tyrosine kinases

• Lammerding et al (2004) and Fonseca et al (2004) mechanosensing in cardiomyocytes

• Scotland et al (2004) TRPV1, 20-HETE and vascular autoregulation

• Ainslie et al (2005) glycocalyx and vascular shear stress

• Cunningham & Gotlieb (2005) review on vascular shear stress and disease

• Lopez-Barneo (2003) oxygen and glucose sensing by carotid body glomus cells

• Lopez-Barneo et al (2004) ion channels and oxygen sensing

• Jonz et al (2004) chemoreceptors in zebrafish gills

• Thebaud et al (2004) potassium channels in ductus arteriosus

• Williams et al (2004) hemoxygenase is the oxygen sensor Hoshi & Lahiri (2004) perspectives

• Tang et al (2004) metabolic regulation of potassium channels (comprehensive review)

• Rutter (2004) visualising insulin secretion

• Burcelin et al (2003) hepatoportal glucose sensor in mice

• Song & Routh (2005) hypothalamic glucose sensors

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Recent references

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Supplementary material: control systems.

Negative feedback (speed, stability and biological effectiveness) universal features of all control systems: comparison of outcome with reference value, error signal, amplification, load, phase shifts, accuracy, speed and stability. Critical damping. Proportional control, integral control, derivative feedback. Why living cells have a multiplicity of control mechanisms (allosteric, covalent modification and genetic) rather then relying on only one technique.

This material is kept in a separate website. We will cover some of it in the lectures if time allows, but in view of the mathematical content we will not set specific examination questions in this area. Feedback loops are fundamental to the operation of sensory transducers and this material could usefully be incorporated into examination answers. Apart from the excellent teams who work on neuromuscular coordination, who clearly do understand the problem, much of the analysis of feedback systems in biology is at a relatively trivial level. This supplementary section tries to redress the balance.

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References

There is no need to read every publication! The most relevant papers are highlighted and all have clickable links. The PubMed link will provide at least the abstract, and may give full text access to some papers, depending on publication date and publisher. Staff and students at the University of Leeds have full text access to all these publications via the second FULL TEXT link, both on- and off-campus. Leeds users will need to quote their library barcode, once per session.

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