Regulation of TRPM8 channel activity

Abstract

Transient Receptor Potential Melastatin 8 (TRPM8) is a Ca(2+) permeable non-selective cation channel directly activated by cold temperatures and chemical agonists such as menthol. It is a well established sensor of environmental cold temperatures, found in peripheral sensory neurons, where its activation evokes depolarization and action potentials. The activity of TRPM8 is regulated by a number of cellular signaling pathways, most notably by phosphoinositides and the activation of phospholipase C. This review will summarize current knowledge on the physiological and pathophysiological roles of TRPM8 and its regulation by various intracellular messenger molecules and signaling pathways.

Figure 1

Regulation of TRPM8 activity. A. Mechanism of desensitization of TRPM8: Ca²⁺ influx through the channel activates a Ca²⁺ sensitive PLC enzyme, presumably a PLCδ isoform, and the resulting depletion of PtdIns(4,5)P₂ limits channel activity, see text (6.2) for details. B. Representative traces from (Yudin et al., 2011) showing desensitization of menthol-induced current in mouse DRG neurons, left panel shows a control cell, right panel shows a cell which was dialyzed with 100 μM diC₈ PtdIns(4,5)P₂.

Figure 2

Cartoon for the regulation of TRPM8 activity by various intracellular signaling pathways that has been implicated in the regulation of these channels. Extracellular signaling molecules activate G- protein coupled receptors (GPCR). Receptors coupling to Gq proteins activate PLCβ-s leading to the formation of IP₃ and DAG, and a reduction in PtdIns(4,5)P₂ (PIP₂) levels. Both IP₃ and Ca²⁺ influx through TRPM8 increases cytoplasmic Ca²⁺, which together with DAG activates PKC, which may inhibit TRPM8 activity. Increased cytoplasmic Ca²⁺ will activate PLCδ isoforms which deplete PIP₂, and Ca²⁺ may also inhibit channel activity through CaM. Activation of Gs coupled receptors will activate adenylate cyclase (AC), which in turn activates protein kinase A (PKA) which may lead to channel inhibition, see text (6.3) for details. iPLA2 enzymes will hydrolyze phospholipids (PL) leading to the formation of lysophospholipids (LPL) and arachydonic acid (AA), see text (6.4) for details.