Transmembrane proteins with unknown function (TMEMs) as ion channels: electrophysiological properties, structure, and pathophysiological roles

Abstract

A transmembrane (TMEM) protein with an unknown function is a type of membrane-spanning protein expressed in the plasma membrane or the membranes of intracellular organelles. Recently, several TMEM proteins have been identified as functional ion channels. The structures and functions of these proteins have been extensively studied over the last two decades, starting with TMEM16A (ANO1). In this review, we provide a summary of the electrophysiological properties of known TMEM proteins that function as ion channels, such as TMEM175 (K_EL), TMEM206 (PAC), TMEM38 (TRIC), TMEM87A (GolpHCat), TMEM120A (TACAN), TMEM63 (OSCA), TMEM150C (Tentonin3), and TMEM43 (Gapjinc). Additionally, we examine the unique structural features of these channels compared to those of other well-known ion channels. Furthermore, we discuss the diverse physiological roles of these proteins in lysosomal/endosomal/Golgi pH regulation, intracellular Ca²⁺ regulation, spatial memory, cell migration, adipocyte differentiation, and mechanical pain, as well as their pathophysiological roles in Parkinson's disease, cancer, osteogenesis imperfecta, infantile hypomyelination, cardiomyopathy, and auditory neuropathy spectrum disorder. This review highlights the potential for the discovery of novel ion channels within the TMEM protein family and the development of new therapeutic targets for related channelopathies.

Fig. 1. Representative structures of each TMEM channel.

Representative structures of each TMEM channel. Red asterisks indicate channel pore(s). a Side view of TMEM175 (K_EL) (PDB; 5VRE) with subunits. Tetrameric structure of TMEM175 (K_EL) from the extracellular (b) and cytosolic (c) images. d Zoomed-in view of the pores of TMEM175 (K_EL). Side view of TMEM206 (PAC) (PDB; 7JNA and 7JNC) at pH 8 (e) and pH 4 (h). Trimeric structure of TMEM206 (PAC) from the extracellular (f, i) and cytosolic (g, j) perspectives at pH 8 and pH 4, respectively. k Side view of TMEM120A (TACAN) (PDB; 7F3T) with the CoASH complex. Dimeric structure of TMEM120A (TACAN) from the extracellular (l) and cytosolic (m) regions. n Side view of TMEM63 (OSCA) (PDB; 6JPF). Dimeric structure of TMEM63 (OSCA) from the extracellular (o) and cytosolic (p) views. q Side view of TMEM38B (TRIC-B) (PDB; 6JYX). Trimeric structure of TMEM38B (TRIC-B) from the extracellular (r) and cytosolic (s) views. t Side view of TMEM87A (GolpHCat) (PDB; 8HSI). u Extracellular GOLD domain of TMEM87A (GolpHCat). v Lumen view of TMEM87A (GolpHCat) with PE.

Fig. 2

Summary of the physiological and pathophysiological properties of TMEM proteins as ion channels.