Evaluating the roles of ion channels in cellular force sensing

ABSTRACT Mechanosensitive ion channels are found across all classes of life, suggesting that cellular force sensing is an ancient sense. In mammals, mechanosensitive ion channels are expressed in many cells and tissues, and disrupting their function can impact an array of physiological processes. The identification and characterisation of mammalian mechanosensitive ion channels has been driven by in vitro patch-clamp electrophysiology studies. However, challenges arise when applying insights from these biophysical measurements across scales. Electrophysiology studies do not capture the complexity of force sensing in vivo, where the nature of mechanical loading, the mechanics of the local environment and the co-expression of accessory molecules can all influence mechanosensitive ion channel function. In addition, a nuanced perspective acknowledging the varying roles that ion channels can play in force-sensing pathways and the distinctions in activation profiles of mechanosensitive ion channels is required to better understand channel-mediated mechanotransduction. In this Opinion article, by synthesising our knowledge of these activation profiles gleaned from in vitro studies, we argue that only by considering mechanosensitive ion channel function within an appropriate cellular and mechanical context will we be able to better understand the roles of this fascinating class of molecule in mammalian cells in vivo.