Heat-Evoked Activation of the Ion Channel, TRPV4

Abstract

The mammalian nervous system constantly evaluates internal and environmental temperatures to maintain homeostasis and to avoid thermal extremes. Several members of the transient receptor potential (TRP) family of ion channels have been implicated as transducers of thermal stimuli, including TRPV1 and TRPV2, which are activated by heat, and TRPM8, which is activated by cold. Here we demonstrate that another member of the TRP family, TRPV4, previously described as a hypo-osmolarity-activated ion channel, also can be activated by heat. In response to warm temperatures, TRPV4 mediates large inward currents in Xenopus oocytes and both inward currents and calcium influx into human embryonic kidney 293 cells. In both cases these responses are observed at temperatures lower than those required to activate TRPV1 and can be inhibited reversibly by ruthenium red. Heat-evoked TRPV4-mediated responses are greater in hypo-osmotic solutions and reduced in hyperosmotic solutions. Consistent with these functional properties, we observed TRPV4 immunoreactivity in anterior hypothalamic structures involved in temperature sensation and the integration of thermal and osmotic information. Together, these data implicate TRPV4 as a possible transducer of warm stimuli within the hypothalamus.

Temperature sensing across species

“…Subsequently, we identified a cold and menthol receptor, TRPM8, from TG neurons using a similar paradigm, thereby establishing that members of the TRP family of ion channels play an important role in thermosensation [47]. Subsequently, four additional TRP channels have been implicated in temperature sensation both in vitro and in vivo, and their properties, along with TRPV1 and TRPM8, can conceivably account for the entire spectrum of perceived temperatures [48][49][50][51][52][53][54][55] (Fig. 3).…”

“…Hence, the cloning and functional analysis of TRPV1 revealed for the first time how sensory neurons detect "moderate" threshold heat responses at the molecular level. Furthermore, several additional TRPV channels are also activated by warmth and heat, suggesting that thermosensory responses to heat are largely mediated by one class of proteins (see below) [48][49][50][52][53][54].…”

“…In vitro, TRPV3 and TRPV4 are activated at temperatures considered warm [49,50,[52][53][54]. TRPV4, a functional orthologue of the C. elegans TRP channel Osm-9 [90,91], was first identified as an osmosensitive ion channel and is activated by decreased osmolarity [92][93][94].…”

“…TRPV4, a functional orthologue of the C. elegans TRP channel Osm-9 [90,91], was first identified as an osmosensitive ion channel and is activated by decreased osmolarity [92][93][94]. However, subsequent studies suggest that TRPV4 is a polymodal receptor, as it can also be triggered at temperatures >25°C and protons [49,50]. The channel is expressed in several tissues, including the preoptic/anterior hypothalamus, keratinocytes, and primary sensory neurons, all regions that serve in various aspects of thermosensation and thermoregulation [50,94,95].…”

“…However, subsequent studies suggest that TRPV4 is a polymodal receptor, as it can also be triggered at temperatures >25°C and protons [49,50]. The channel is expressed in several tissues, including the preoptic/anterior hypothalamus, keratinocytes, and primary sensory neurons, all regions that serve in various aspects of thermosensation and thermoregulation [50,94,95]. TRPV3, alternatively, is activated by a number of natural plant products that produce a sensation of warmth, including camphor and the active components of oregano, thyme, and cloves [83,96].…”