BIOC3800 Exam 2005 John Illingworth’s Marking Scheme
Discuss with examples the biochemical mechanisms responsible for sensory adaptation.
The lecture “handout” was an electronic reading list, with links to key papers. Students were expected to read a reasonable proportion, and advised to concentrate on the biochemical mechanisms responsible for the following features of biological transducers:
· very sensitive
· huge dynamic range
· negative feedback systems
· adaptation to ongoing stimuli
· report changes rather than the steady state
· selection and filtering of information from the beginning
· conversion from analog to digital encoding at an early stage of the transduction pathway
It is not possible to describe the adaptation mechanisms without refering to the underlying transduction processes, so 50% of the marks are for adaptation and 50% for transduction. The students had a lot of work to do, and a lot of information to remember, so I was relaxed about minor errors and omissions. The question did not specify how many examples they should give, and with more examples I would expect less detail about each one.
Bacterial chemotaxis:
Wadhams GH and Armitage JP (2004) Making sense of it all: bacterial chemotaxis. Nat Rev Mol Cell Biol 5, 1024-1037.
A good answer would include the basic transduction pathway in E. coli or B. subtilis (which are partly the opposite way round) including periplasmic binding proteins, methyl accepting chemotaxis proteins, CheA, CheB, CheR, CheW, CheY, CheZ, reversing the rotary flagellar motor, tumbling and free swimming.
Students should realise that MCPs may combine several contradictory input signals, and that the degree of methylation is the adaptation mechanism, that tracks and compensates for the net attractant signal. The delays inherent in the feedback system through CheB allow CheY to transduce the first derivative of the attractant signal, and this is used to control the motor.
Taste:
Zhang Y et al (2003) Coding of sweet, bitter, and umami tastes: different receptor cells sharing similar signaling pathways. Cell 112, 293-301.
Prawitt D et al (2003) TRPM5 is a transient Ca2+-activated cation channel responding to rapid changes in [Ca2+]i Proc Natl Acad Sci U S A 100, 15166-15171.
Sweet, bitter, and umami taste receptors are distinct GPCRs signaling through PLCb2 which increases intracellular [Ca++] and activates TRPM5, which is a monovalent cation channel. Excess Ca++ is inhibitory, and this contributes to adaptation, which is not well understood. TRPM5 inherently responds to rapid changes in [Ca++] rather than the steady state.
Olfaction:
Matthews HR and Reisert J (2003) Calcium, the two-faced messenger of olfactory transduction and adaptation. Curr Opin Neurobiol 13, 469-475.
Olfactory transduction takes place in the cilia of the olfactory receptor cells, each of which expresses only one from a large family of odourant receptors. Odourant binding activates adenyl cyclase through a G protein system. The rise in cAMP concentration opens cyclic nucleotide-gated channels, and an influx of Na+ and Ca++ initiates the electrical response to odour stimulation.
Increased ciliary [Ca++] has two opposing effects: activation of an excitatory Cl− channel, and negative feedback on two stages of the odour transduction mechanism. Ca++ calmodulin rapidly inhibits the calcium entry channel, and CaM kinase slowly reduces the activity of adenyl cyclase. These two processes are thought to explain fast and slow components of the olfactory adaptation mechanism
Hearing:
Fettiplace R and Ricci AJ (2003) Adaptation in auditory hair cells. Curr Opin Neurobiol 13, 446-451.
Gillespie PG and Cyr JL (2004) Myosin-1c, the hair cell’s adaptation motor. Annu Rev Physiol 66, 521-545.
Chan DK and Hudspeth AJ (2005) Ca2+ current-driven nonlinear amplification by the mammalian cochlea in vitro Nat Neurosci 8, 149-155.
The mammalian cochlea contains both inner and outer hair cells. The inner row are the most sensitive transducers, but the outer rows are more motile. The outer cells respond to nervous stimulation and may be involved in selective amplification or attenuation of sounds. Both sets of cells are bathed in endolymph and subject to an endocochlear potential.
Mechanical bending of hair bundles towards their tallest edge opens mechanically gated ion channels near the tips of the component stereocilia. This allows an influx of K+ and Ca++ ions that depolarize the hair cell. Deflection of the stereocilia exerts tension on the tip links that transmit force to the mechanoelectrical transducer TRPA1 channel. To keep the system within a narrow operating range these channels are subject to multiple Ca++-controlled mechanisms of adaptation.
Fast adaptation requires direct interaction of Ca++ with TRPA1 channels to modulate their open probability. The diffusion distance is only 15–35 nm so this process completes in 1 msec. This fast Ca++-dependent channel reclosure may be involved in amplification, which requires cycle-by-cycle force generation. Hair cell bodies are also motile and contain prestin, whose shape responds to membrane potential in about 10 msec. Slow adaptation takes 20 msec and requires a Ca++–dependent motor, myosin-1c, to tension the elastic elements in series with the TRPA1 channel. cAMP shifts the “channel open” probability along the displacement axis, with no effect on fast adaptation, perhaps through phosphorylation of the TRPA1 channel or the myosin motor by protein kinase A.
In addition, reflex relaxation of the muscle that tensions the maleus, incus and stapes protects the delicate hearing mechanism in very noisy environments.
Vision:
Fain GL et al (2001) Adaptation in vertebrate photoreceptors. Physiol Rev 81, 117-151.
Hardie RC & Raghu P (2001) Visual transduction in Drosophila. Nature 413, 186-193.
Cronin MA et al (2004) Light-dependent subcellular translocation of Gqa in Drosophila photoreceptors is facilitated by the photoreceptor-specific myosin III NINAC. J Cell Sci 117, 4797-4806.
mammals / drosophilaphotoreceptor / rod & cones (modified cilia) / rhabdomeres (microvilli)
dark condition / depolarised, secreting glutamate / polarised, not secreting
initial light effect / meta-rhodopsin II activates transducin / meta-rhodopsin II activates G protein
first termination / opsin and trans retinal dissociate / no dissociation
retinal recycling / slow, involves pigment cells / fast, involves red light
G protein / releases free Gαt subunits / releases free Gαq subunits
target enzyme / cGMP phosphodiesterase / phospholipase C β4
response termination / RGS-9 + PDE-γ regulate GTPase activity / RGS(?) + PLC regulate GTPase activity
2nd messenger / cGMP falls on illumination / DAG (?) rises on illumination
plasmalemma / cGMP-gated TRP channels close / DAG-gated (?) TRP channels open
final light effect / PRC hyperpolarises, stops secreting / PRC depolarises, starts secreting
light adaptation 1 / Ca++ falls; guanyl cyclase activity rises / Ca++ rises; +ve feedback within microvillus
light adaptation 2 / rhodopsin kinase inactivates opsin / rhodopsin kinase inactivates opsin
light adaptation 3 / arrestin closes down rhodopsin / arrestin closes down rhodopsin
light adaptation 4 / translocate proteins between compartments / translocate proteins between compartments
light adaptation 5 / switch from rods to less sensitive cones / all rhabdomeres have similar sensitivities
light adaptation 6 / close pupil / Ca++-dependent movement of pigment granules
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