Exciting times in sensory transduction from A(drian) to Z

We can all appreciate the importance of sensing our external and internal environments – functions carried out by sensory nerves supplying essentially every organ and tissue of our body. Sensory signals warn of impending tissue damage or danger, yet also provide pleasure, e.g. the beauty of a sunset and the pleasure of a caress. Below conscious perception, sensory nerves also regulate essential visceral functions including bladder, bowel, breathing and blood pressure. Loss of sensory functions due to injury or disease is debilitating and devastating, for individuals and society. Deservingly so, the exploration of mechanisms of sensory transduction has received extensive attention from scientists. Professor Edgar Douglas Adrian, in the first half of the 20th century, launched the field of sensory transduction. The subject of this Classical Perspective (Adrian, 1926a) was the first in a series of papers addressing the nature of action potential discharge recorded from a variety of sensory nerves (Adrian, 1926b; Adrian & Zotterman, 1926a,b). As they say in the wine business, 1926 was a very good year! This first paper described the use of a triode thermionic valve amplifier coupled to a capillary electrometer to record action potentials from sensory nerves with previously unattainable precision. The electrometer resulted in much less distortion than the string galvanometer commonly used at the time, the latter being limited by the mass of the string and consequently high inertia of the moving parts. The use of a reliable valve amplifier solved a major limitation of the electrometer, its low sensitivity. The improvement in the method was substantial. It enabled, for the first time, quantitative measurements of action potential discharge from frog, cat and rabbit sensory nerves evoked by relatively mild, physiologically relevant stimuli (Adrian, 1926a). Not surprisingly, and as is often the case in science, the improved method led to numerous discoveries. Beyond the importance of the technological advance, one must not overlook the astute observations of sensory nerve function reported in this classic paper. Activity was recorded from mechanoreceptor afferents innervating skeletal muscle during muscle stretch, from cutaneous afferents stimulated by forceps pinch and pin prick (nociceptors), and from visceral afferents in the vagus and ‘cardiac depressor’ nerves (Adrian, 1926a). The relation between stimulus strength and discharge frequency, the all-or-none nature of action potential discharge, and spike frequency adaptation were understood. The presence of pulmonary stretch receptor afferents in the vagus nerve and blood pressure sensitive afferents in the ‘cardiac depressor’ nerve were described. This paper was soon followed by more detailed reports of nerve impulses recorded from single fibres innervating muscle spindles of the frog (Adrian & Zotterman, 1926a), and cutaneous afferents in cats responsive to touch and pressure (Adrian & Zotterman, 1926b) and painful stimuli (Adrian, 1926b). Later studies addressed afferent single-fibre activity in the vagus nerves and its influence on respiration (Adrian, 1933), and multifibre activity in efferent sympathetic nerves (Adrian et al. 1932). Investigators and particularly students interested in sensory transduction are strongly encouraged to read the Adrian papers. His extraordinary skills in experimental observation and data interpretation are illuminated by the exquisite detail and clarity of his writing. He took care to not overstate the results and exercised caution in interpreting them. His conclusions and speculations were particularly insightful, and were confirmed and proven true in later studies. Professor Adrian's breakthrough discoveries earned him the Novel Prize in Physiology or Medicine, which he shared with Sir Charles Sherrington in 1932. How has our knowledge of sensory transduction progressed since the time of Adrian? Although a major advance, the amplifier/electrometer used by Adrian was not sensitive enough to record from single non-myelinated C-fibres. Further improvements in instrumentation were needed before detailed information on this important class of nerve fibre could be obtained. Adrian recognized the need for deformation of the sensory nerve endings (or end organ) to activate mechanosensitive afferents, but he was uncertain as to how deformation led to initiation of the nerve impulse (Adrian & Zotterman, 1926b). We now know that this is achieved by a depolarizing generator or receptor potential localized at or near the nerve terminals or end organ (Katz, 1950; see review by Grigg, 1986). Investigation into molecular mechanisms mediating mechanically induced depolarization has evolved and has utilized diverse experimental approaches. These include: (1) patch-clamp recordings of currents through mechanosensitive ion channels permeable to cations, first achieved in embryonic chick skeletal muscle (Guharay & Sachs, 1984); (2) the discovery of genes/molecules involved in mechanosensation in lower ‘model’ organisms (e.g. C. elegans) using genetic screens (Driscoll & Chalfie, 1991; Huang & Chalfie, 1994); (3) the identification of evolutionarily conserved mammalian homologues as candidate mechanosensitive channels (Canessa et al. 1993); and (4) the demonstration that genetic disruption or pharmacological blockade of candidate channels alters responses of sensory neurones to mechanical stimuli in vitro and in vivo. Members of three channel subfamilies – the epithelial sodium channels (ENaCs), acid sensing ion channels (ASICs), and transient receptor potential (TRP) channels – have emerged as contributing to mechanoelectrical transduction in a variety of different types of mammalian sensory nerves (Drummond et al. 1998; Price et al. 2000, 2001; Garcia-Anoveros et al. 2001; Jones et al. 2005; Page et al. 2005). Recent reviews on these topics are available (Hamill & Martinac, 2001; Welsh et al. 2002; Goodman & Schwarz, 2003; Chapleau et al. 2007). Clearly, exciting times continue in the field of sensory transduction! Professor Adrian would surely agree that today's rapid pace of gene discovery and technological development combined with carefully performed, well-designed physiological studies will lead to major advances in our understanding of sensory transduction in the years to come.