Variable Threshold of Trigeminal Cold-Thermosensitive Neurons Is Determined by a Balance between TRPM8 and Kv1 Potassium Channels

Abstract

Molecular determinants of threshold differences among cold thermoreceptors are unknown. Here we show that such differences correlate with the relative expression of I KD , a current dependent on Shaker-like Kv1 channels that acts as an excitability brake, and I TRPM8 , a cold-activated excitatory current. Neurons responding to small temperature changes have high functional expression of TRPM8 (transient receptor potential cation channel, subfamily M, member 8) and low expression of I KD . In contrast, neurons activated by lower temperatures have a lower expression of TRPM8 and a prominent I KD . Otherwise, both subpopulations have nearly identical membrane and firing properties, suggesting that they belong to the same neuronal pool. Blockade of I KD shifts the threshold of cold-sensitive neurons to higher temperatures and augments cold-evoked nocifensive responses in mice. Similar behavioral effects of I KD blockade were observed in TRPA1 Ϫ/Ϫ mice. Moreover, only a small percentage of trigeminal cold-sensitive neurons were activated by TRPA1 agonists, suggesting that TRPA1 does not play a major role in the detection of low temperatures by uninjured somatic cold-specific thermosensory neurons under physiological conditions. Collectively, these findings suggest that innocuous cooling sensations and cold discomfort are signaled by specific low-and high-threshold cold thermoreceptor neurons, differing primarily in their relative expression of two ion channels having antagonistic effects on neuronal excitability. Thus, although TRPM8 appears to function as a critical cold sensor in the majority of peripheral sensory neurons, the expression of Kv1 channels in the same terminals seem to play an important role in the peripheral gating of cold-evoked discomfort and pain.

Functional profiling of neurons through cellular neuropharmacology

“…2D) that the complement of voltage-gated K channels in the two subtypes of menthol-sensitive cells likely differ. Notably, other investigators have shown that sensory trigeminal neurons responsive to innocuous cool temperatures (low-threshold cold thermoreceptors) show high expression of TRPM8 and low expression of K V 1 channels, whereas neurons responsive to noxious cold temperatures (high-threshold cold thermoreceptors) show low expression of TRPM8 and high expression of K V 1 channels, with K V 1 acting as an excitability brake in high-threshold, cold-sensitive neurons (14).…”

“…Although this approach is not unprecedented, typically only a few pharmacological agents have been used to profile neuronal subtypes in a single experiment (13)(14)(15). We show the feasibility of applying many challenge compounds in a single experiment, and we have discovered that certain types of challenge compounds elicited a far greater spectrum of phenotypic responses than predicted.…”

Labeled lines meet and talk: population coding of somatic sensations

“…This threshold is lower than that of many human C2 fibers (> 30°C) (18). However, in vivo cold sensitivity of sensory neurons can be modulated by other factors, such as the expression of two potassium channels, TREK1 and TRAAK (35)(36)(37). Genetic studies have established an essential role of TRPM8 in sensing innocuous cold (38)(39)(40)(41).…”

N-Glycosylation of TRPM8 Ion Channels Modulates Temperature Sensitivity of Cold Thermoreceptor Neurons

“…In fact, the lack of N-glycosylation in Kv1.1 and Kv1.2 affects the function of these potassium channels (19,53). These channels are closely related to the establishment of the temperature activation threshold displayed by trigeminal sensory neurons, being the molecular entities underlying the current I KD , which acts as an excitability brake in cold thermoreceptor neurons (29,38). Specifically, the absence of N-glycosylation of Kv1 channels caused a net decrease in its activity (19,53).…”