Mammalian TRP ion channels are insensitive to membrane stretch

Abstract

TRP channels of the transient receptor potential ion channel superfamily are involved in a wide variety of mechanosensory processes, including touch sensation, pain, blood pressure regulation, bone loading and detection of cerebrospinal fluid flow. However, in many instances it is unclear whether TRP channels are the primary transducers of mechanical force in these processes. In this study, we tested stretch activation of eleven TRP channels from six mammalian subfamilies. We found that these TRP channels were insensitive to short membrane stretches in cellular systems. Furthermore, we purified TRPC6 and demonstrated its insensitivity to stretch in liposomes, an artificial bilayer system free from cellular components. Additionally, we demonstrated that, when expressed in C. elegans neurons, mouse TRPC6 restores the mechanoresponse of a touch insensitive mutant but requires diacylglycerol for activation. These results strongly suggest that the mammalian members of the TRP ion channel family are insensitive to tension induced by cell membrane stretching and, thus, are more likely to be activated by cytoplasmic tethers or downstream components and to act as amplifiers of cellular mechanosensory signaling cascades.

TRPC Channels in Proteinuric Kidney Diseases

“…Moreover, a point mutation in TRPC6 eliminates mechanical activation of cationic currents in podocytes without affecting activation by GPCRs or cell-permeable DAG analogs [34]. Although the role of mechanical stretch in activation of TRPC family members has recently been questioned [37], these data are consistent with the notion that stretch-induced TRPC6 activation in podocytes is mediated by both receptor-dependent and receptor-independent mechanisms.…”

Human TRPA1 is an inherently mechanosensitive bilayer-gated ion channel

“…Taken together, it is suggested that oxidative stress and perhaps other environmental factors (e.g., pH, Ca 2+ , polyphosphates) alone or in combination can shape the response to mechanical stimuli by shifting hTRPA1 into a force-to-lipid sensitive protein conformation. Thus, the concerns raised regarding experimental condition and TRPA1 thermosensitivity (5,6) may also be valid in studies of TRPA1 mechanosensitivity, and explain why TRP channel mechanical activity cannot always be detected at a cellular level or in artificial lipid bilayers (7).…”

“…The proposal by David Corey and colleagues that mouse TRPA1, with its large intracellular N-terminal ankyrin repeat domain (N-ARD), could be a mechanosensor involved in hearing has triggered a great interest in TRPA1 as a potential primary mechanosensor within the mammalian sensory nervous system (4)(5)(6). Although a role for TRPA1 in mammalian normal and nociceptive signaling in response to mechanical stimuli seems convincing, no evidence of TRPA1 intrinsic mechanosensitivity has been provided (3,(5)(6)(7).…”

Peripheral Mechanobiology of Touch—Studies on Vertebrate Cutaneous Sensory Corpuscles

“…However, it has not been fully determined whether these ion channels are mechanosensors or are only required for mechanosensation [ 81 ]. Recently, it was demonstrated that mammalian members of different families of TRP channels are insensitive to membrane stretch, suggesting that they do not represent the primary mechanotransducers [ 82 ]. In spite of this, evidence is accumulating that members of TRP families participate in mechanosensing.…”