The Function And Mechanism Research Of TMC Protceins In Determining The Membrane Excitability&Ray Neurons In Mechanosensation In C.elegans

Mutations in transmembrane channel-like(TMC)proteins TMC1 and TMC2 cause auditory and vestibular deficits and deafness in mammals.However,their physiological functions are controversial and precise action modes are elusive.Here,we discover that both TMC-1 and TMC-2 are required for normal egg-laying behavior in C.elegans.Mutations in these two TMC proteins cause membrane hyperpolarization and disrupt the rhythmic calcium activities in both neurons and muscles involved in egg-laying.Mechanistically,TMC proteins enhance membrane depolarization through sodium-leak currents and ectopic expression of TMC-1 in TMC-negative neurons results in the sodium-dependent membrane depolarization.Furthermore,transgenic expression of mammalian TMC homologs can largely rescue the egg-laying defects observed in tmc mutant worms.Therefore,we have identified an unexpected role of TMC proteins in determining membrane excitability.Our results may provide mechanistic insights into the functions of TMC 1 and TMC2 in mammalian hearing loss.Mechanotransduction is crucial for touch sensation,hearing,proprioception and pain.In C.elegans,male ray neurons have been implicated to be involved inmechanosensation required for mating behavior.However,whether ray neurons directly sense mechanical stimulation is not well understood,and the underlying molecular mechanisms have yet to be identified.Using in vivo calcium imaging,herewe record touch-induced calcium responses in male ray neurons.Our data demonstrate that ray neurons are sensitive to mechanical stimulation in a neurotransmitter-independent manner.PKD-2,a putative sensor component for both mechanosensation and chemosensation in male specific neurons,is not required for touch-induced calcium responses in RnB neurons,whereas TRPV channel OSM-9 shapes the kinetics of touch-induced calcium responses.We further show that mechanosensation of RnB neurons is likely mediated by amiloride-sensitive DEG/ENaC channel.These observations will lay a foundation for better understanding the molecular mechanisms of mechanosensation.