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Elena Gracheva

Elena Gracheva
Program
Beckman Young Investigators

Award Year
2013

Institution
Yale University

Email:
elena.gracheva@yale.edu

Website:
http://bbs.yale.edu/people/elena_gracheva.profile

Research Title:
Molecular basis of reversible hypothermia in mammalian hibernators

Abstract:
Detection and avoidance of potentially damaging temperatures is crucial for survival. At the same time, certain mammals, including desert-dwelling camels and diurnal sciurid rodents, have evolved the ability to withstand temperature extremes and are thus able to live in environments otherwise inhospitable to many species. Here, using thirteen-lined ground squirrels (Ictidomys tridecemlineatus) as a laboratory model, we sought to explore the molecular basis for heat tolerance at the level of the somatosensory system. In mammals, noxious heat is detected by a specific subpopulation of primary afferent neurons that express TRPV1, a polymodal ion channel that is activated by a variety of noxious stimuli including temperatures above ~42°C, capsaicin from chili peppers, as well as protons. However, for squirrels, our behavioral experiments and live-cell ratiometric calcium imaging of dissociated primary afferent neurons revealed significant decreases in temperature sensitivity of the channel. Furthermore, electrophysiological recordings from squirrel TRPV1 in heterologous systems demonstrated a dramatic modality-specific decrease in response to heat, thus providing a potential molecular mechanism for decreased thermosensitivity of the animals. Interestingly, we observed a similar phenomenon when we examined the TRPV1 orthologue from the famously heat-tolerant wild Bactrian camel (Camelus ferus). Thermosensitivity of both squirrel and camel TRPV1 could be fully regained via substitution of a single conserved amino acid residue in the N-terminal ankyrin repeat domain—highlighting remarkable plasticity of the TRPV1 thermosensing function. Together, our data suggest that, in order to cope with elevated temperatures, camels and squirrels both target the temperature-sensitivity of TRPV1—a channel particularly amendable to evolutionary adaptations due to its apparent low-cost functional plasticity.

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