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Review
. 2020 Dec;14(1):413-420.
doi: 10.1080/19336950.2020.1841419.

The cool things to know about TRPM8!

Mircea Iftinca  1 , Christophe Altier  1
Affiliations
Review

The cool things to know about TRPM8!

Mircea Iftinca et al. Channels (Austin). 2020 Dec.

Abstract

Transient receptor potential melastatin 8 (TRPM8) channels play a central role in the detection of environmental cold temperatures in the somatosensory system. TRPM8 is found in a subset of unmyelinated (C-type) afferents located in the dorsal root (DRG) and trigeminal ganglion (TG). Cold hypersensitivity is a common symptom of neuropathic pain conditions caused by cancer therapy, spinal cord injury, viral infection, multiple sclerosis, diabetes, or withdrawal symptoms associated with chronic morphine treatment. Therefore, TRPM8 has received great attention as a therapeutic target. However, as the activity of TRPM8 is unique in sensing cool temperature as well as warming, it is critical to understand the signaling transduction pathways that control modality-specific activity of TRPM8 in healthy versus pathological settings. This review summarizes recent advances in our understanding of the mechanisms involved in the regulation of the TRPM8 activity.

Keywords: G proteins; PIP2; Transient receptor potential channel subfamily M (melastatin) member 8 (TRPM8); protein kinase C (PKC).

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Conflict of interest statement

No potential conflict of interest was reported by the authors.

Figures

Figure 1.
Figure 1.
Identified signaling pathways involved in TRPM8 channel regulation. 1 – Activation of PLCδ4 by calcium influx leads to PIP2 depletion and inhibition of TRPM8; 2 – Gq-coupled receptor-mediated stimulation of PLCβ leads to PIP2 depletion and inhibition of TRPM8. 3 – In response to the stimulation of the bradykinin receptor (B2R), Gαq directly binds to and inhibit TRPM8; 4 – DAG and calcium influx mediate the activation of PKC, which contributes to a Ca2+ mediated desensitization of TRPM8; 5 – Activation of Gs-coupled receptors leads to a PKA-mediated inhibition of TRPM8; 6 – Testosterone activates TRPM8 directly or indirectly through the AR signaling pathway that involves Src, ERK and MAPK. Abbreviations: AR-androgen receptor, DAG – diacylglycerol, ERK – extracellular signal-regulated kinase, GPCR – G protein-coupled receptor, IP3 – inositol trisphosphate, MAPK – mitogen-activated protein kinase, PIP2 – phosphatidylinositol bisphosphate, PKA – protein kinase A, PKC – protein kinase C, PLC-phospholipase C
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