The Ca 2+ and ADP ribose (ADPR)-activated cation channel TRPM2 is the closest homolog
of the cold sensor TRPM8 but serves as a deep-brain warmth sensor. To unravel the
molecular mechanism of heat sensing by the TRPM2 protein, we study here temperature
dependence of TRPM2 currents in cell-free membrane patches across ranges of agonist
concentrations. We find that channel gating remains strictly agonist-dependent even
at 40°C: heating alone or in combination with just Ca 2+ , just ADPR, Ca 2+ + cyclic
ADPR, or H 2 O 2 pretreatment only marginally activates TRPM2. For fully liganded
TRPM2, pore opening is intrinsically endothermic, due to ~10-fold larger activation
enthalpy for opening (~200 kJ/mol) than for closure (~20 kJ/mol). However, the temperature
threshold is too high (>40°C) for unliganded but too low (<15°C) for fully liganded
channels. Thus, warmth sensitivity around 37°C is restricted to narrow ranges of agonist
concentrations. For ADPR, that range matches, but for Ca 2+ , it exceeds bulk cytosolic
values. The supraphysiological [Ca 2+ ] needed for TRPM2 warmth sensitivity is provided
by Ca 2+ entering through the channel’s pore. That positive feedback provides further
strong amplification to the TRPM2 temperature response (Q 10 ~ 1,000), enabling the
TRPM2 protein to autonomously respond to tiny temperature fluctuations around 37°C.
These functional data together with published structures suggest a molecular mechanism
for opposite temperature dependences of two closely related channel proteins.
