Heat-Evoked Activation of the Ion Channel, TRPV4

TLDR

The nervous system monitors temperature, and members of the TRP ion channel family—including heat‑activated TRPV1 and TRPV2 and cold‑activated TRPM8—serve as thermal transducers. This study shows that TRPV4, previously known for hypo‑osmolarity activation, is also heat‑activated. Heat activates TRPV4 in Xenopus oocytes and HEK293 cells, producing large inward currents and calcium influx at temperatures below those that activate TRPV1; these responses are ruthenium‑red‑sensitive, enhanced by hypo‑osmotic and diminished by hyper‑osmotic conditions, and TRPV4 is expressed in hypothalamic regions involved in temperature regulation, suggesting it functions as a warm stimulus transducer.

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 <i>Xenopus</i> 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.