Switch on pop-ups!
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
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.
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
|High performance ‘external’ sensors||Slower, less adaptive ‘internal’ mechanisms|
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.
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
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.
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.
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.
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