TRPM Channels in Human Diseases.

Ivanka Jimenez,Felipe Eltit,Felipe Simon,Yolanda Prado,Felipe Marchant,Carolina Otero,Claudio Cabello-Verrugio,Oscar Cerda

doi:10.3390/cells9122604

Abstract

The transient receptor potential melastatin (TRPM) subfamily belongs to the TRP cation channels family. Since the first cloning of TRPM1 in 1989, tremendous progress has been made in identifying novel members of the TRPM subfamily and their functions. The TRPM subfamily is composed of eight members consisting of four six-transmembrane domain subunits, resulting in homomeric or heteromeric channels. From a structural point of view, based on the homology sequence of the coiled-coil in the C-terminus, the eight TRPM members are clustered into four groups: TRPM1/M3, M2/M8, M4/M5 and M6/M7. TRPM subfamily members have been involved in several physiological functions. However, they are also linked to diverse pathophysiological human processes. Alterations in the expression and function of TRPM subfamily ion channels might generate several human diseases including cardiovascular and neurodegenerative alterations, organ dysfunction, cancer and many other channelopathies. These effects position them as remarkable putative targets for novel diagnostic strategies, drug design and therapeutic approaches. Here, we review the current knowledge about the main characteristics of all members of the TRPM family, focusing on their actions in human diseases.

Highlights

Ion channels are proteins composed of a pore that allows for passive and regulated ion flux through biological membranes as determined by an electrochemical gradient [1,2]
This effect of TRPM3 and autophagy in clear cell renal cell carcinoma (ccRCC) has been confirmed by the effects of mefenamic acid, a non-steroidal anti-inflammatory that was described as a specific blocker of TRPM3 [129]
We recently demonstrated that the role of Transient Receptor Potential Melastatin 7 (TRPM7) in the progression of endotoxemia is that the channel expression and activity increase the secretion of pro-inflammatory cytokines like tumor necrosis factor-a (TNF-α), IL-1β, IL-6 and IL-12 without changing the anti-inflammatory cytokine production

Summary

Introduction

Ion channels are proteins composed of a pore that allows for passive and regulated ion flux through biological membranes as determined by an electrochemical gradient [1,2]. The N-terminus is composed of 4 melastatin homology regions and one homology region or pre-S1 domain (Figure 1a, red boxes) These regions form a pocket which has been suggested to play an important role in external stimuli sensing and channel assembly [49]. The coiled-coil domain (cc) allows for interactions between channel subunits for tetrameric complex assembling and contains specific motifs that modulate pore gating (Figure 1a, blue boxes) [50]. Three members of this family, TRPM2, TRPM6 and TRPM7, present enzymatic activity in their C-terminus.

General Properties and Distribution

Activation and Inhibition

Physiological Function and Role in Diseases

Conclusions