lab research

The sense of touch is unique in perceiving stimuli both physical (temperature, mechanical) and chemical (compounds that cause pain, itch, et cetera) in nature. In each modality, touch neurons distinguish noxious (painful) from innocuous stimuli, and the sensitization of touch neurons in response to injury and inflammation is the basis for many clinically-relevant chronic pain states. The molecules that mediate detection of touch stimuli have been a long-standing mystery. Our lab has identified and characterized ion channels activated by distinct changes in thermal energy (in the noxious to innocuous range), thus functioning as the molecular thermometers of our body. A subset of these same ion channels also act as polymodal chemosensors, playing an essential role in pain and inflammation. Small molecule antagonists of TRPA1, one of the ion channels identified in the Patapoutian lab, are currently in clinical studies.

Mechanotransduction is perhaps the last sensory modality to be understood at the molecular level. Ion channels that sense mechanical force are postulated to play critical roles in sensing touch/pain (somatosensation), sound (hearing), sheer stress (cardiovascular tone), and more; however, the identity of such ion channels has remained elusive. We identified Piezo1 and Piezo2, mechanically-activated cation channels that are expressed in many mechanosensitive cell types. Recently, we have shown that mouse Piezo1 and Piezo2 are essential mechanical transducers in red blood cells and vascular endothelial cells and in touch and proprioceptive neurons, respectively. We are also searching for novel ion channels involved in translating physical stimuli into chemical signals. For example, we recently co-discovered SWELL1 (LRRC8A), an essential component of the volume-regulated ion channel (VRAC). First described over 30 years ago, VRAC is required for maintaining cell volume in response to osmotic challenges. We demonstrated that SWELL1 and related subunits are sufficient to form ion channels in lipid bilayers and that osmolality gradients open SWELL1-containing ion channels via a decrease in intracellular ionic strength, a consequence of cell-swelling.

cartoon of noxious stimuli sensed by TRPA1

TRPA1 acts as a nocisensor

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