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Review
. 2011 Jun;300(6):R1278-87.
doi: 10.1152/ajpregu.00631.2010. Epub 2011 Mar 16.

Scraping through the ice: uncovering the role of TRPM8 in cold transduction

Daniel D McCoy  1 , Wendy M Knowlton, David D McKemy
Affiliations
Review

Scraping through the ice: uncovering the role of TRPM8 in cold transduction

Daniel D McCoy et al. Am J Physiol Regul Integr Comp Physiol. 2011 Jun.

Abstract

The proper detection of environmental temperatures is essential for the optimal growth and survival of organisms of all shapes and phyla, yet only recently have the molecular mechanisms for temperature sensing been elucidated. The discovery of temperature-sensitive ion channels of the transient receptor potential (TRP) superfamily has been pivotal in explaining how temperatures are sensed in vivo, and here we will focus on the lone member of this cohort, TRPM8, which has been unequivocally shown to be cold sensitive. TRPM8 is expressed in somatosensory neurons that innervate peripheral tissues such as the skin and oral cavity, and recent genetic evidence has shown it to be the principal transducer of cool and cold stimuli. It is remarkable that this one channel, unlike other thermosensitive TRP channels, is associated with both innocuous and noxious temperature transduction, as well as cold hypersensitivity during injury and, paradoxically, cold-mediated analgesia. With ongoing research, the field is getting closer to answering a number of fundamental questions regarding this channel, including the cellular mechanisms of TRPM8 modulation, the molecular context of TRPM8 expression, as well as the full extent of the role of TRPM8 in cold signaling in vivo. These findings will further our understanding of basic thermotransduction and sensory coding, and may have important implications for treatments for acute and chronic pain.

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Figures

Fig. 1.
Fig. 1.
Temperature preference and temperature avoidance in transient receptor potential (TRP)M8 knockout mice. In the 2-temperature discrimination assay, mice are placed in a chamber in which the temperature of the floor plates can be controlled. In the preference assay (A), the proportion of the testing period that the mice spend on each plate is measured with a 50% reading for any given plate indicating that the mouse does not discriminate between the 2 surfaces and spends equal amounts of time on each plate. Such is the case when both plates are set to 30°C for both wild-type (WT) and TRPM8 null (KO) mice. As the temperature of one of the plates is lowered, WT mice spend a greater proportion of the testing period on the 30°C plate, while KO mice display defects in thermal discrimination by showing no preference for the 30°C plate. KO mice do show some preference for the 30°C plate when the test plate is set to 5°C; however, their responses are still reduced compared with WT mice (8, 43). This can be explained by the presence of two partially overlapping drives: a cold discomfort avoidance drive, which is dependent on skin thermoceptors and increases as temperature decreases, and a second drive to maintain proper bodily temperatures by reducing the thermoregulatory burden, probably autonomic and perhaps dependent on the tonic activation of enteric warm receptors (thermoregulatory drive). At warm or mildly cool temperatures, this second drive does not significantly affect animal behavior, thus the behavior is driven solely by the discomfort drive. However, at noxious cold temperatures, this autonomic drive would engage and direct the behavior of both WT and KO mice to spend more time in the thermoregulation-favorable environment. Yet since the KO mice still show a deficit at noxious cold, this thermoregulatory drive would not be strong enough to totally compensate for the loss of the discomfort drive. If the same data are quantified for thermal avoidance (B), a clear picture of the role of TRPM8 in sensory discrimination emerges. Thermal avoidance is quantified as the number of times the mouse crosses the plate-plate boundary, with WT mice showing dramatically reduced numbers of crossings as the test plate temperature is lowered. The KO mice, on the other hand, continue crossing at a high rate regardless of the temperature of the test plate (43). Since the autonomic thermoregulatory drive in (A) would not be involved in crossing behavior, only the discomfort drive would be influencing this behavior. Since KO mice show no changes in crossings across the temperatures tested, this indicates that TRPM8 is responsible for the detection of both innocuous and noxious cold through the skin.
Fig. 2.
Fig. 2.
Model for innocuous cool vs. noxious cold TRPM8 afferent subtypes. Cold-sensitive neurons respond to different threshold stimuli and are characterized by differential molecular landscapes. A: low threshold (LT) cold-sensitive neurons respond to innocuous stimuli starting ∼25°C, while high threshold (HT) cold-sensitive neurons respond to noxious stimuli starting ∼15°C. B: LT neurons are predominantly controlled by heightened TRPM8-mediated currents due to high channel expression and/or activity regulated by high levels of phosphatidylinositol-(4,5)-bisphosphate (PIP2) (the substrate for PLCδ). Potassium brake currents associated with voltage-gated potassium channels belonging to the Kv1 family are reduced relative to HT neurons, resulting in more easily excitable cells. Unknown voltage-gated sodium channels may also be involved in LT cold transduction. HT neurons have reduced TRPM8-mediated currents due to low expression and/or activity facilitated by lower levels of PIP2. They are strongly influenced by heightened potassium brake currents coming from channels such as Kv1, TREK, and TRAAK. HT cold-sensing neurons also express the voltage-gated sodium channel Nav1.8 (a cold-insensitive channel), which directly facilitates action potential generation at lower temperatures where other sodium channels would be inhibited.
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