No studies on TRPM4 in cancer mouse models have been published. the TRPM4 antibody, M4P. Additionally, we provide an overview of TRPM4 in human malignancy and discuss TRPM4 as a diagnostic marker and anticancer drug target. strong class=”kwd-title” Keywords: ion channel, cancer, drug target, proliferation, migration, calcium, prognostic marker 1. Introduction Transient receptor potential (TRP) family is a large superfamily of widely expressed ion channels, which mainly conduct cations, including Ca2+, Mg2+, and Na+. TRP channels are responsible for a broad range of cellular functions, and many of these channels regulate intracellular Ca2+ homeostasis and signaling. TRP channels are divided into six mammalian subfamilies based on their structural homology, and each family differs in its mode of activation [1]. Transient receptor potential melastatin 4 (TRPM4) belongs to the TRPM channel subfamily. TRPM4 and TRPM5, the closest homologue of TRPM4, differ from the other TRP family members because they do not conduct Ca2+ but only monovalent cations [2,3]. Intracellular Ca2+ directly activates TRPM4, which then conducts an influx of Na+ [4]. In 2017 and 2018, almost simultaneously, four impartial groups published cryo-EM structures of TRPM4, revealing both a nucleotide-binding domain name (NBD) that binds ATP and is located in the N-terminal and a Ca2+ binding site in the transmembrane domain name [5,6,7,8]. The Ca2+-activated activity of TRPM4 can be altered by ATP, IP3, calmodulin, and protein kinase C-dependent phosphorylation [9,10]. TRPM4 was shown to be voltage-dependent, as membrane potential strongly modulates its activity [11]. Positive potential increases TRPM4 conductivity. However, changes in membrane potential RIPGBM are not sufficient to activate the channel. TRPM4 is usually widely expressed in various organs, although its expression is the highest in the prostate, colon, and heart [2,11]. TRPM4 is also expressed in immune cells (dendritic, mast, and Th1 and Th2 cells) [12,13,14], as well as in the central nervous system [15]. Hence, TRPM4s broad expression patterns support its potential implications in the physiological functions of different RIPGBM cells, tissues, and organs. Indeed, TRPM4 has been linked to a range of physiological processes, many involving fundamental cellular functions. Dysregulations of TRPM4 by either altered expression levels or mutations have been linked to several pathological conditions, including cardiac disorders [16,17,18,19,20,21,22,23,24], immune diseases [13,14,25,26], and neurological disorders [27,28,29]. In addition, TRPM4 was suggested to be an interesting pharmacological target for the treatment of mucus-related diseases, such as cystic fibrosis, as it was recently shown to be involved in goblet cell mucin secretion [30]. TRPM4 has been suggested to play a role in insulin secretion in pancreatic -cells [31]. However, another study using TRPM4 knockout mice reported no differences in glucose-induced insulin release compared to wild-type mice [14]. Lately, growing interest has been directed toward TRPM4 and its role in several types of cancer [32,33,34,35,36,37,38,39,40,41]. TRPM4 contributes to several cancer hallmark functions, such as cell migration, proliferation, and the epithelial to mesenchymal transition (EMT). In this paper, we review the emerging data about TRPM4s involvement in cancer hallmark functions, as well as the correlation of TRPM4 expression with patient outcome. We summarize the possible mechanisms of action, such as altered intracellular Ca2+ signaling, covalent modifications (glycosylation and phosphorylation), and protein interaction partners and discuss recent advances with new TRPM4 blockers, including the M4P antibody and small molecule inhibitors. 2. General Mechanisms of TRPM4 Upon activation, TRPM4 conducts Na+ ions into the cell. This influx of positive ions depolarizes the plasma membrane and thereby decreases the driving pressure for Ca2+ RIPGBM entry via store-operated Ca2+ entry (SOCE) and other Ca2+ entry pathways [42]. SOCE has been linked to several fundamental cellular processes, including gene expression. Alterations in SOCE Ca2+ signaling were shown to contribute to several cancer hallmark functions, e.g., decreased apoptosis and increased proliferation and migration [43,44,45,46,47,48,49,50,51]. In nonexcitable cells, SOCE is the main Ca2+ entry pathway. A plethora of extracellular stimuli induce intracellular IP3 production and, subsequently, endoplasmic reticulum (ER) Ca2+ store depletion. The drop in ER luminal Ca2+ concentration sequentially activates the unfolding of stromal conversation molecule 1 (STIM1) and, subsequently, activates the store-operated Orai1 Ca2+ Rabbit polyclonal to IL11RA channels [52]. Anticancer drugs may involve changes in Ca2+ signaling [53,54]; moreover, membrane transport proteins contribute to chemoresistance in several types of cancer [55]. Although TRPM4 is usually nonpermeable to Ca2+, Na+ influx via TRPM4 decreases membrane potential and results in a decrease in intracellular Ca2+ signaling in many different cells, including rat dental pulp stem cells, various immune cells, and cancer cells [2,12,13,14,41,56,57]. However, an increase in SOCE by TRPM4 expression has also been observed [35,58]. Clearly, a mechanism fundamentally.