Functional biology of ion channels : a review

Over the past few decades, a great deal of attention has been focused on discovering the protein partners that form mechano- electrical transduction (MeT) channels in somatic mechanoreceptors. Two classes of ion channel proteins are leading candidates: amiloride-sensitive channel (ASCs) and transient receptor potential (TRP) channel proteins. Here, we surveyed the literature to establish that most, if not all mechanoreceptor neurons in mice express multiple ASC and TRP channel proteins. But, the landscape of ion channel co-expression in mechanoreceptor neurons is only beginning to be mapped. Future work aimed at refining such maps for mammalian mechanoreceptor neurons will be critical for deeper understanding. Also, each of these potential MeT channel subunits operates within a large company of other ion channel actors that increase the complexity, flexibility, and robustness of somatosensory neuron function. Recently, two additional classes of membrane proteins (Piezo and TMC) have been linked to mechano-transduction. This situation is likely to exist in other mechanoreceptor neurons, including those responsible for touch and pain sensation in mammals.


Introduction
via several neurotransmitter-receptor systems that have been shown to affect the spinal processing of All sensory neurons are alike.Each sensory nociceptive input.Excitatory neurotransmitters (e.g., neuron detects a physical stimulus and produces an substance P), are active in spinal cord and enhance pain electrical signal that gives rise to behavioural responses, transmission.The inhibitory elements are the opioids, conscious perceptions, or both.Many operate near the the α2-adrenergic fibres, serotoninergic and adenosiphysical limits of detection and operate over a dynamic nergic receptors.Endogenous neurotransmitters work range of several orders of magnitude.These properties on dorsal horn neurons to inhibit excitatory transmitter suggest that they are endowed with a detector, an release and consequently to decrease pain and perception.amplifier, and mechanisms for gain control.One of the The skin is the largest sensory surface, extending most striking and well understood examples is the nearly two square meters on an average.Mechanoability of photoreceptors to detect single photons while receptor neurons are principal actors in this theatre.retaining sensitivity to light intensities that vary by They are responsible not only for detecting mechanical nine orders of magnitude [1].
cues, but also for encoding and transmitting all relevant Nociception is a physiological process which information to the central nervous system.Every moment involves transduction, transmission, modulation and of every day, our skin and its embedded sensory neurons perception of the noxious stimuli.Chemical mediators are bombarded with mechanical cues that we experience are important components of the nociceptive reflex and as pleasant or painful.Knowing the difference between offer a target of pharmacologic modulation [2].
innocuous and noxious mechanical stimuli is critical Nociceptors are specialized nerve fibres that have their for survival and relies on the function of mechanodendritic endings in peripheral tissue, with several receptor neurons that vary in their size, shape, and different subtypes identified.The fastest of the nerve sensitivity [3].Their performance is shaped by ion fibres are the large diameter myelinated A-α sensory channels that include, but are not limited to, sensory fibers which are involved with the sensations of touch, transduction channels.Agents that activate or inhibit pressure, etc. Somewhat slower are the thinly myelimechanoreceptor neurons can exert their influence by nated A-α fibres which are involved in sharp physiologic acting on channels other than transduction channels.and acute pain.C-fibres have small diameter, are For example, naked mole rats are insensitive to the unmyelinated and, are very slow conductors of persistent skin acidification that is a feature of their nociception and are involved in dull, aching chronic environment.These animals have acid-gated ion channels pain.Chemical modulation of pain transmission occurs + (ASICs) with a similar sensitivity to protons (H ) as + those found in mice.However, the voltage-gated Na channels expressed in their C-fibre noci-ceptors are hypersensitive to inhibition by protons and this inhibition counterbalances the excitation due to ASIC activation, electroplax revealed a protein of more than 1800 amino rendering animals insensitive to acidifi-cation [4].
acid residues in length, arranged in four repeated Thus, the difference in nociceptor sensitivity arises domains (I-IV).These four domains are arrayed + around a central pore, as observed in more recent cryofrom variation in voltage-gated Na sodium channels electron microscopic images (Fig. 1) [8].that are essential for action potential generation rather than any variation in sensory trans-duction.

Phospholipids and voltage sensor function: An
Studies on ion channels essential role for phospholipids in the structure and + function of voltage-gated Na channels was suggested Electrical signalling in biology depends on the by early biochemical experiments in which specific rapid, highly sensitive response of voltage-gated ion phospholipid combinations were required for channels to small changes in membrane potential.
reconstitution of ion conductance, voltage-dependent Voltage-gated ion channels derive their steep voltage toxin binding, and voltage-dependent gating of purified dependence of activation from electrically driven + Na channels.Consistent with this requirement for movement of positively charged amino acid residues specific lipids, the high-resolution structure of a outward across the membrane in response to depolari-KV1.2/2.1 chimera revealed intrinsically bound zation.Voltage-gated ion channels generate electrical phospholipid molecules [9].These bound phospholipids signals in species from bacteria to human being.Their are seen around the waist of the protein where it voltage-sensing modules are responsible for initiation contacts the phospholipid bilayer and also in the of action potentials and graded membrane potential internal and external vestibules in the voltage sensor changes in response to synaptic input and other [9].The phospholipid head groups are in position to physiological stimuli [5].In their landmark papers on + serve as ion pair partners of gating charges at the voltage-clamp analysis of Na currents in the squid intracellular and extracellular surfaces of the memgiant axon, Hodgkin and Huxley predicted that activation + brane, but not within the core of the voltage-sensing of the Na conductance must involve movement of module.Evidence that phospholipid head groups can charged particles, now termed ''gating charges,'' across affect voltage-dependent gating supports an important the membrane electrical field [6].The gating charge role for these bound lipids in voltage sensor function movements' estimates indicate movement of 12-16 [10,11].positive charges outward across the electric field + +

Studies on mechanoreceptor neurons
during gating of Na or K channels [7].

Discovery of the voltage sensors and gating charges
Though mechanoreceptor neurons were first of ion channels: Biochemical studies using neurotoxins studied more than 75 years ago [12], the events that link as molecular probes led to discovery of the voltagesensory stimulation to neuronal activation are only + gated Na channel protein and reconstitution of its beginning to be understood.Genetic screens for voltage-dependent gating and ion conductance from animals defective in touch sensation have revealed purified protein and phospholipid components.critical roles for genes encoding TRP channels and Determination of the primary structure of the voltage-ASCs in behavioural responses to mechanical inputs + gated Na channel from Electrophorus electricus (Fig. 2).We review data demonstrating that TRP