BIOC3800 Sensory Transducers

1. BIOC3800Sensory Transducers Dr. J.A. Illingworth

2. Course information • There is a website to accompany this part of the course, http://www.bmb.leeds.ac.uk/illingworth/BIOC3800/index.htm with model answers, self-assessment tests and clickable links to recent papers and other sources of information. • Examination questions on sensory transduction will allow you to select your own illustrations and examples, but we expect you to supply details about examples you select. • Aim to spend about 3 hours private study on each lecture, reading papers and preparing summary diagrams that could be produced in the written examinations. • Try to see the big picture without becoming bogged down in a mass of very minor details.

3. Some textbooks • Many general physiology texts include an account of the special senses, but unavoidable production delays mean that even the latest textbooks are several years out of date. We suggest: • 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 - an excellent book, but getting dated • Fundamental Neuroscience. Squire LR et al (Academic Press, 2008.) ISBN 9780123740199 detailed account in chapters 24 – 27

4. Previous examination questions • This is a large and rapidly changing field, so we set wide-ranging examination questions that allow you considerable choice. We expect you to illustrate your answers with details of the specific examples that you select. • 2005: "Discuss with examples the biochemical mechanisms responsible for sensory adaptation." • 2006: "Discuss the roles of motor proteins in sensory transduction and adaptation." • 2007: "Discuss the roles of primary cilia in sensory transduction." • 2008: "Discuss the biological importance of sensory adaptation and outline the adaptation mechanisms in a variety of biological transducers." • 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." • 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." • The question in 2011 will follow a similar pattern to previous years.

5. Common features of sensory transducers Sensory transducers report biologically relevant information to their owners. External sensors 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 start of the path • convert from analog signals to faster, low-noise digital encoding at an early stage of the transduction pathway

6. Common features (continued) In contrast to the previous slide, those sensors that monitor the body’s internal environment often • have more time • require less sensitivity • respond in a narrow physiological range • show less adaptation towards ongoing situations • 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 signaling components

7. Sensory adaptation

8. High performance ‘external’ sensors Vision Hearing and balance Smell Mechanosensors (some of these are slow, but muscle spindles and pressure transducers may provide rapid and precise responses to external events.) Slower, less adaptive ‘internal’ mechanisms Taste (plus a family of related sensors lower in the GI tract that rarely reach consciousness) Monitoring systems for oxygen, carbon dioxide, glucose, small molecules, temperature, osmolarity and fluid flow have limited range and respond more slowly to stimulation. Compare and contrast…

9. Closed loop control systems 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 system subtracts C from R so as to generate anerror 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.

10. Control systems (2) Every closed loop system needs a reference value which provides a target to aim for. This is always true, even for complex 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: thermostat • varying reference but constant load: audio amplifier • varying reference and varying load: brain & muscles

11. Control systems (3) • 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 “external” sensory transducers the reference value is definitely NOT constant, because it is the input signal from the outside world. These transducers commonly track this varying input signal, and thereby generate first derivative, logarithmic and filtered information more appropriate to the needs of the organism.

12. Bacterial chemotaxis (1) • Bacteria are too small to sense chemical gradients directly. • They discover the best direction by making small random movements in arbitrary directions, and keep going for longer if things improve. • E. coli cells have typically half a dozen flagellae, which are attached to the cell by extremely flexible universal joints, and independently rotated by motors in the cell wall. • The flagellae are "handed" like corkscrews. If they all rotate anti-clockwise (viewed from the far end) they mesh together and form an efficient propulsive unit • If one or more flagellae adopt a clockwise rotation then the flagellar bundle flies apart and the cell tumbles randomly in the growth medium.

13. Bacterial chemotaxis (2) • Wadhams & Armitage (2004) Making sense of it all: Bacterial Chemotaxis. Nature Reviews in Molecular Cell Biology 5, 1025 – 1037. • Baker et al (2006) Signal transduction in bacterial chemotaxis. BioEssays 28.1, 9 – 22. • Thomas et al (2006) The Three-Dimensional Structure of the Flagellar Rotor from a Clockwise-Locked Mutant of Salmonella enterica Serovar Typhimurium. J. Bacteriology, 188(20), 7039-7048. • Rao et al (2008) The three adaptation systems of Bacillus subtilis chemotaxis.Trends in Microbiology 16, 480 – 487.

14. Bacterial chemotaxis (3)

15. Bacterial chemotaxis (4)

16. Bacterial chemotaxis (5) • Histidine–aspartate-phosphorelay systems • HAP systems have at least two components — a dimeric histidine protein kinase (HPK) and a response regulator (RR). The Arabidopsis thaliana genome has 16 genes for HPK and 24 RR homologues. • HAP systems rely on the trans-autophosphorylation of a His residue that resides in one monomer of the HPK dimer by the γ-phosphoryl group of an ATP molecule that is bound to the kinase domain of the other monomer. • This phosphoryl group is then transferred to an Asp residue on a separate RR protein to alter its activity and generate a response

17. Bacterial chemotaxis (6) • Some histidine - aspartate phosphorelay systems

18. Bacterial chemotaxis (7) • Chemotactic signals are detected by transmembrane chemoreceptors — the methyl-accepting chemotaxis proteins (MCPs). • An adaptor protein, CheW, helps link the MCPs to the cytoplasmic HPK, CheA, and two RRs compete for binding to CheA. • One RR is a single-domain, flagellar motorbinding protein, CheY, whereas the other, CheB, functions as a methylesterase and controls the adaptation of the MCPs. • Phosphorylated CheY (CheY–P) binds the switch protein FliM on the flagellar motor, causing temporary reversal in the direction of motor rotation.

19. Bacterial chemotaxis (8) • The phosphatase CheZ dephosphorylates CheY–P and allows rapid signal termination. • PBP – periplasmic ligand binding protein

20. Bacterial chemotaxis (9) • Increased attractant inhibits autophosphorylation of CheA, which reduces CheY–P and hence the frequency of motor switching. This causes the bacterium to swim in a positive direction for longer. • CheB phosphorylation and methylesterase activity is also reduced, which allows the constitutive methyltransferase CheR to methylate the MCPs. • Highly methylated MCPs are better able to stimulate CheA autophosphorylation, which returns to the pre-stimulus level. • MCP methylation therefore tracks the attractant level after a slight delay. This allows the system to calculate the vital first derivative of the attractant concentration.

21. Bacterial chemotaxis (10) • Regulation of chemotaxis in B. subtilis is more complex than in E. Coli, and three overlapping control systems are involved. • CheY-P binding causes counter-clockwise rotation of the motor in B. subtilis and clockwise rotation in E. coli • Counter-clockwise rotation correlates with runs and clockwise rotations with tumbles in both organisms • In E. coli, binding of attractant to the receptors inhibits CheA kinase activity, thereby reducing CheY-P concentrations and increasing the likelihood of a run. • In B. subtilis, attractant activates the CheA kinase, thereby increasing CheY-P concentration and increasing the likelihood of a run.