Navigating the Controversies: Role of TRPM Channels in Pain States

Abstract

Chronic pain is a debilitating condition that affects up to 1.5 billion people worldwide and bears a tremendous socioeconomic burden. The success of pain medicine relies on our understanding of the type of pain experienced by patients and the mechanisms that give rise to it. Ion channels are among the key targets for pharmacological intervention in chronic pain conditions. Therefore, it is important to understand how changes in channel properties, trafficking, and molecular interactions contribute to pain sensation. In this review, we discuss studies that have demonstrated the involvement of transient receptor potential M2, M3, and M8 channels in pain generation and transduction, as well as the controversies surrounding these findings.

Keywords: G-protein coupled receptors; TRPM2; TRPM3; TRPM8; analgesia; nociception.

Figure 1

Topology of TRPM channels. TRPM channels have 4 melastatin-homology regions (MRH) followed by a pre-S1. The S1–S6, α-helices form the transmembrane-spanning channel segments. Pore is located between S5 and S6. The C-terminus contains the TRP and the coiled-coil (CC) domain. Additionally, TRPM2 channels have a NUDT9 homology (NUDT9-H) domain, and TRPM6 and TRPM7 have a serine/threonine protein kinase domain (α-Kinase) in their C-terminus. Figure modified from [16].

Figure 2

Activation of TRPM2 induces CXCL8 production. In monocytes, TRPM2 channels, when activated by H₂O₂, allow the influx of Ca²⁺, which activates PyK2, Ras, ERK, and finally the transcription factor NF-κB. NF-κB is translocated to the nucleus and increases the transcription of CXCL8. This promotes neutrophil infiltration to the injury site.

Figure 3

TRPM3 channels have two permeation pathways. The canonical pathway is located at the pore of the channels and transports Na⁺ and Ca²⁺ ions, and the alternative pore is located at the S4 segment where Na⁺ ions are transported.

Figure 4

TRPM3 channel activity and expression are regulated by diverse proteins. (a) TRPM3 channels are molecular targets of the Gβγ subunit release after GPCR activation. (b) The activating transcription factor 4 (ATF4) increases TRPM3 channel membrane expression in a KIF17-dependent manner.