Global versus local mechanisms of temperature sensing in ion channels

Abstract

Ion channels turn diverse types of inputs, ranging from neurotransmitters to physical forces, into electrical signals. Channel responses to ligands generally rely on binding to discrete sensor domains that are coupled to the portion of the channel responsible for ion permeation. By contrast, sensing physical cues such as voltage, pressure, and temperature arises from more varied mechanisms. Voltage is commonly sensed by a local, domain-based strategy, whereas the predominant paradigm for pressure sensing employs a global response in channel structure to membrane tension changes. Temperature sensing has been the most challenging response to understand and whether discrete sensor domains exist for pressure and temperature has been the subject of much investigation and debate. Recent exciting advances have uncovered discrete sensor modules for pressure and temperature in force-sensitive and thermal-sensitive ion channels, respectively. In particular, characterization of bacterial voltage-gated sodium channel (BacNa) thermal responses has identified a coiled-coil thermosensor that controls channel function through a temperature-dependent unfolding event. This coiled-coil thermosensor blueprint recurs in other temperature sensitive ion channels and thermosensitive proteins. Together with the identification of ion channel pressure sensing domains, these examples demonstrate that "local" domain-based solutions for sensing force and temperature exist and highlight the diversity of both global and local strategies that channels use to sense physical inputs. The modular nature of these newly discovered physical signal sensors provides opportunities to engineer novel pressure-sensitive and thermosensitive proteins and raises new questions about how such modular sensors may have evolved and empowered ion channel pores with new sensibilities.

Disease-associated mutations in TRPM3 render the channel overactive via two distinct mechanisms

“…While the mechanism of temperature activation of TRP channels is not fully understood (Clapham and Miller, 2011;Islas, 2017;Arrigoni and Minor, 2018;Castillo et al, 2018), large scale unbiased mutagenesis studies on TRPV1 (Grandl et al, 2010) and TRPV3 (Grandl et al, 2008) show that mutations in the pore region and the outer portion of S6 in these channels selectively abolished heat-, but not agonist-induced channel activation. The P1090/1092Q mutation in TRPM3 is located in the outer portion of S6, and it had a stronger effect on heat activation than the V990/9992M mutation, therefore it is possible that the primary effect of the P1090/1092Q mutation is increasing heat sensitivity.…”

Thermosensitivity of the voltage-dependent activation of calcium homeostasis modulator 1 (calhm1) ion channel

“…Thermosensitivity is a key property of various ion channels, such as the vanilloid-type transient receptor potential channel (TRPV), Ca 2+ -activated Cl − channels, voltage-dependent proton channels, and the TWIK-related K + channel (TREK) [12–17]. Here, we investigated the effects of temperature on the voltage-dependence and kinetics of the calhm1 current ( I calhm1 ) in human embryonic kidney cells (HEK293) cells using patch-clamp techniques.…”

Limits of Temperature Adaptation and Thermopreferendum

“…A tropical tilapia Alcolapia grahami from the lake Magadi (Kenya) lives in rapid stream sources with water temperature of up to 43 o C. The value of the critical heat maximum Ctmax, measured according to the methodology of critical temperatures [33], was 45.6 o C for this population [67]. Considering that at temperatures above 43 o C the tertiary and quaternary structure of many proteins is violated [68,69], these results should be treated with caution. If an upper temperature limit is taken as 43 o C and thermopreferendum, as 37 o C, then a lower temperature limit, in analogy with mammalians [70,71], will amount about 30 o C. The metabolism rate measured in these tilapias, exceeds the parameters ever recorded in ectotherms and lays within the basic range of metabolic rates of small mammals [67].…”