Abstract
Animals sense various ranges of temperatures, pressure and irritants through skin-nerve pathway at the maximum level, pain sensation. Molecular mechanism under the response to physical factors is thus essential for understanding pain. Transient receptor potential vanilloid 4 (TRPV4) is a family of capsaicin receptor encoding a cation channel activated by cell swelling. We early cloned the gene and made its deficient mice, TRPV4-/-. Based on the findings from molecule to mouse, TRPV4 plays a key role in sensing of certain ranges of these stimuli and I here summarize putative molecular mechanisms. TRPV4 is located in DRG, nerve endings and deep keratinocytes. In vivo, TRPV4-/- becomes unable to respond to cutaneous pressure in a range of 80-300 mmHg. TRPV4 current or a rise in intracellular Ca2+(iCa) was observed in response to shear stress less than 10 mPa. The deformity of cell surface transmits the signal through a coiled-coil protein or lipid-based signal transduction. On the other hand, TRPV4 plays a cardinal role in warmth sensation. Neuronal activity in the femoral nerve revealed that number and activity of neurons decreased in response to a warm temperature in TRPV4-/- mice. TRPV4-/- mice displayed a significantly longer latency to escape from the hotplates at 35-45 oC when hyperalgesia was induced by carrageenan. Single channel analysis of TRPV4 suggested that warming did not directly activate TRPV4 in inside-out patches but that an intracellular heat-sensing protein may help for TRPV4 to cluster. Although the protein is not yet isolated, we could suggest in collaboration with Dr. Koide (National Institute of Genetics) that a mouse lacking this protein reveals a heat-insensitive phenotype. [Jpn J Physiol 55 Suppl:S10 (2005)]
