Molecular Basis of Somatic Sensation

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DESCRIPTION (provided by applicant): Mechanotransduction is the process whereby a cell transforms a mechanical force into an electrochemical signal. For instance, somatosensory neurons of the dorsal root and trigeminal ganglia detect deformations to the body and signal the senses of proprioception touch and pain. These are among the least understood senses, both at the physiological and at the molecular level. To find an ion channel that might mediate cutaneous mechanosensation in mammals, we looked for homologs of the degenerin ion channels that mediate this sense in worms. We found one, BnaC1apha that is expressed by DRG neurons, is transported distally but not centrally, and is specifically located in cutaneous sensory endings. Mutant animals lacking BNaC1 have reduced touch sensitivity, suggesting that BNaC1 is part of the mechanosensory channel. BnaC1alpha in mechanosensory DRG neurons forms heteromultimers with the related proteins DRASIC and/or BNaC2/ASIC. Recently, we also found a putative scaffolding protein (PICK1) that binds to BnaCl alpha, is present in touch terminals, and thus may be an additional component of a mechanotransducing complex for touch. We now need to know whether BnaC1alpha and PICK1 might be involved in mechanosensation in proprioceptive end organs such as muscle spindles as well as in the high frequency Pacinian corpuscles. We will test this with antibodies against BnaC1alpha and PICK1. We need to understand the directional transport of BnaC1alpha (and perhaps PICK1) from DRG cell bodies to the periphery, a novel mode of protein sorting in DRG. We will use viral transfection of DRG with tagged BnaC1alpha, and mutate its intracellular domains to affect its transport. A peripheral targeting domain might be shared with other sensory proteins. Finally, we need to identify other potential elements of the touch transduction complex, and will do so by identifying proteins from somatosensory ganglia that (1) bind BnaC1alpha, DRASIC, or BNaC2/ASIC, or (2) are homologous to other nematode proteins necessary for touch. These studies will help elucidate the molecular mechanisms for mechanotransduction in touch, proprioception, and certain forms of pain.