Piezo2 tension sensitivity and its modulation by alternative splicing

Piezo2 is a force-gated ion channel that functions as a sensor of mechanical touch, proprioception, lung inflation, and gut transit. Human Piezo2 contains seven domains that are alternatively spliced in a tissue-specific fashion resulting in the expression of at least 22 distinct variants. Despite the relevance of Piezo2 in human physiology, its sensitivity to membrane tension, and how this fundamental biophysical property is affected by alternative splicing, are unknown. Here, we use cell-attached pressure-clamp electrophysiology combined with differential interference contrast microscopy to quantify the response of Piezo2 to membrane tension and identify the alternatively spliced exon 35 as a domain sufficient to confer high sensitivity to membrane tension and cellular indentation. We further show that physiological variants of Piezo2 sense mechanical forces with distinct sensitivities and dynamic ranges. Together, our findings rationalize how Piezo2 variants may fulfill distinct physiological functions required for somatosensation and interoception.