Biophysical Society Conference | Tahoe 2022

Molecular Biophysics of Membranes

Monday Speaker Abstracts

DECIPHERING WHERE AND HOW TOUCH HAPPENS Miriam B. Goodman 1 ;

1 Stanford University, Department of Molecular and Cellular Physiology, Stanford, CA, USA Touch is the first sense to develop and it is often sense the last to fade. Ion channels, the first responders of touch sensation, convert the mechanical energy delivered during touch into electrical signals within milliseconds or faster. At least three classes of proteins form these specialized mechanoelectrical transduction (MeT) complexes: DEG/ENaC/ASIC sodium channels, TMC cation channels, TRP cation channels, and Piezo cation channels. The DEG/ENaC/ASIC and TMC channels are thought to activate via a force-from-filament activation mode, while the others operate in a force-from-lipid mode. Regardless of which force-dependent gating model applies to a given channel, we hypothesize that the subcellular position of MeT channels is tightly regulated and helps to determine the threshold and dynamic range of touch sensation. Despite the importance of the subcellular distribution of MeT channels for touch sensation, however, little is understood about how their positions are established and stabilized within somatosensory neurons. As a first step toward addressing this question, we focused on the junction between somatosensory neurons and surrounding epidermal cells. In many animals, including humans and nematodes, this junction is filled by a specialized extracellular matrix or basal lamina. Using touch receptor neurons in Caenorhabditis elegans, we show that the MeT channel MEC-4 is anchored to stable and punctate mechanosensory complexes in vivo and that these complexes also contain the ancient and conserved basal lamina proteins, laminin and nidogen. All three proteins fail to coalesce into discrete, stable structures in dissociated neurons and in touch-insensitive mec-1, mec-9 and mec-5 mutants lacking secreted ECM proteins. By contrast, only MEC-4, but not laminin or nidogen, is destabilized in animals in which the somatosensory neurons secrete a mutant MEC-1 carrying missense mutations in the C-terminal Kunitz domain. Thus, neuron-epidermal cell interfaces are instrumental in mechanosensory complex assembly and function. Drawing on computational modeling, we propose that these complexes concentrate mechanical stress into discrete foci and they enhance touch sensitivity. Consistent with this idea, loss of nidogen reduces the density of mechanoreceptor complexes, the amplitude of the touch-evoked currents they carry, and touch sensitivity in parallel. These findings imply that somatosensory neurons secrete proteins that actively repurpose the basal lamina to generate special-purpose mechanosensory complexes responsible for touch sensation.

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