Dual amplification strategy turns TRPM2 channels into supersensitive central heat detectors

Bartók, Ádám and Csanády, László (2022) Dual amplification strategy turns TRPM2 channels into supersensitive central heat detectors. PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA, 119 (48). e2212378119. ISSN 0027-8424

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Abstract

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.

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