Coordinated regulation of PIEZO2 by alternative splicing, post‐translational modification, membrane trafficking and protein partners

PIEZO2 is a principal mechanotransduction channel for somatosensory and interoceptive signalling, yet coordinated regulation of this channel remains poorly understood. Emerging work reveals that multilayered regulation of PIEZO2 coordinates the expression, function, gating and membrane localization of the channel to maintain homeostatic mechanosensitivity. This review highlights evidence for several interdependent mechanisms by which PIEZO2 is regulated. Specifically, alternative splicing generates PIEZO2 splice isoforms with distinct functions, post-translational modifications modulate gating kinetics of the protein, and a growing network of interacting and non-interacting protein partners influence PIEZO2 mechanosensitivity. Evidence that highlights the clinical importance of PIEZO2 regulation is presented. PIEZO2 variants cause congenital mechanosensory/proprioceptive disorders, often with respiratory complications; and altered PIEZO2 activity or expression has been implicated in tactile allodynia/mechanical hypersensitivity and reported across multiple cancers. Overall, this review integrates current knowledge of PIEZO2 regulation and dysregulation, highlighting how convergent mechanisms shape tissue-specific and context-specific mechanosensitivity. A central conclusion is that PIEZO2 functions as the core of a larger mechanotransduction module and, therefore, the behaviour of the channel cannot be understood by examination of the pore alone. Discussion of these emerging studies highlights an opportunity to gain deeper insight into the regulatory mechanisms of PIEZO2 channels in vivo and may reveal strategies to selectively modulate PIEZO2-dependent mechanosensation in disease.