Caldendrin Is a Repressor of PIEZO2 Channels and Touch Sensation in Mice

Abstract

The sense of touch is crucial for cognitive, emotional, and social development and relies on mechanically activated (MA) ion channels that transduce force into an electrical signal. Despite advances in the molecular characterization of these channels, the physiological factors that control their activity are poorly understood. Here, we used behavioral assays, electrophysiological recordings, and various mouse strains (males and females analyzed separately) to investigate the role of the calmodulin-like Ca2+sensor, caldendrin, as a key regulator of MA channels and their roles in touch sensation. In mice lacking caldendrin (Cabp1KO), heightened responses to tactile stimuli correlate with enlarged MA currents with lower mechanical thresholds in dorsal root ganglion neurons (DRGNs). The expression pattern of caldendrin in the DRG parallels that of the major MA channel required for touch sensation, PIEZO2. In transfected cells, caldendrin interacts with and inhibits the activity of PIEZO2 in a manner that requires an alternatively spliced sequence in the N-terminal domain of caldendrin. Moreover, targeted genetic deletion of caldendrin inPiezo2-expressing DRGNs phenocopies the tactile hypersensitivity of completeCabp1KO mice. We conclude that caldendrin is an endogenous repressor of PIEZO2 channels and their contributions to touch sensation in DRGNs.Significance StatementOur sense of touch allows us to discriminate shapes and textures, as well as influences learning, emotion, and social relationships. Touch sensation relies on the activity of mechanically activated ion channels in peripheral sensory neurons, but the molecular mechanisms that regulate this process are poorly understood. Our study identified a requirement for the neuronal Ca2+sensor caldendrin as a key regulator of PIEZO2 mechanically activated channels and their roles in touch sensation. Our findings establish a molecular pathway that could be targeted in novel therapies for conditions that involve aberrant responses to touch such as autism spectrum disorder and neuropathic pain.