4TM-TRPM8 channels are new gatekeepers of the ER-mitochondria Ca2+ transfer

Abstract

Calcium (Ca) release from the endoplasmic reticulum plays an important role in many cell-fate defining cellular processes. Traditionally, this Ca release was associated with the ER Ca release channels, inositol 1,4,5‑triphosphate receptor (IPR) and ryanodine receptor (RyR). Lately, however, other calcium conductances have been found to be intracellularly localized and to participate in cell fate regulation. Nonetheless, molecular identity and functional properties of the ER Ca release mechanisms associated with multiple diseases, e.g. prostate cancer, remain unknown. Here we identify a new family of transient receptor potential melastatine 8 (TRPM8) channel isoforms as functional ER Ca release channels expressed in mitochondria-associated ER membranes (MAMs). These TRPM8 isoforms exhibit an unconventional structure with 4 transmembrane domains (TMs) instead of 6 TMs characteristic of the TRP channel archetype. We show that these 4TM-TRPM8 isoforms form functional channels in the ER and participate in regulation of the steady-state Ca concentration ([Ca]) in mitochondria and the ER. Thus, our study identifies 4TM-TRPM8 isoforms as ER Ca release mechanism distinct from classical Ca release channels.

Mitochondria-Associated Endoplasmic Reticulum Membranes in Cardiovascular Diseases

“…Recently, a new family of TRPM8 channel isoforms as functional ER Ca 2+ release channels expressed in MAMs has been identified (Bidaux et al, 2018). We also confirmed that SR-resident TRPM8 participated in the regulation of cellular and mitochondrial Ca 2+ homeostasis in the VSMCs.…”

Differential Effect of Glucose on ER-Mitochondria Ca2+ Exchange Participates in Insulin Secretion and Glucotoxicity-Mediated Dysfunction of β-Cells

“…2) They were performed in the absence of extracellular Ca 2+ in order to exclude an activation of P2X receptors by ATP and an influx of Ca 2+ that was reported to participate in glucose-mediated mitochondrial Ca 2+ rise (35). 3) We used ATP to stimulate ER-mitochondria Ca 2+ exchange in INS-1E cells, as classically performed in numerous cell types (17,27,29,(38)(39)(40). Moreover, ATP is a physiological extracellular signaling molecule of b-cells, arising from presynaptic terminals innervating the islets (as acetylcholine), from insulin secretion vesicles, or from connexin hemichannels and pannexin channels (41), and activation of P2YR was known to stimulate insulin secretion in a glucose-dependent manner (42).…”

Autophagy and mitophagy in cancer metabolic remodelling

“…Receptor and TRPM8 in the ER membrane [94,95] by regulating tumour-stroma interaction [34,35]. Therefore it is important to clarify the effects of metabolic drugs on autophagy in tumours and to consider their association with autophagy inhibitors.…”