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Biochim Biophys Acta Mol Cell Res. 2018 Jul;1865(7):981-994. doi: 10.1016/j.bbamcr.2018.04.007. Epub 2018 Apr 18.

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

Author information

1
Univ Lille, Inserm U1003, PHYCEL Laboratory, Physiologie Cellulaire, F-59000 Lille, France; Laboratoire de Physique des Lasers, Atomes et Molécules, Equipe Biophotonique Cellulaire Fonctionnelle, UMR 8523, Parc scientifique de la Haute Borne, Villeneuve d'Ascq, France; Univ Lyon, CarMeN Laboratory, INSERM, INRA, INSA Lyon, Université Claude Bernard Lyon 1, 69550 Bron, France; Hospices Civils de Lyon, Groupement Hospitalier EST, Département de Cardiologie, IHU-OPERA Bâtiment B13, 69550 Bron, France. Electronic address: gabriel.bidaux@univ-lyon1.fr.
2
Univ Lille, Inserm U1003, PHYCEL Laboratory, Physiologie Cellulaire, F-59000 Lille, France; Laboratory of Molecular Pharmacology and Biophysics of Cell Signalling, Bogomoletz Institute of Physiology, Kiev, Ukraine.
3
Univ Lille, Inserm U1003, PHYCEL Laboratory, Physiologie Cellulaire, F-59000 Lille, France.
4
Université de Tours, GICC, PATCH Team, Tours, France.
5
Inserm, UMR 1069, Université François Rabelais Tours, Tours, France.
6
Univ Lyon, CarMeN Laboratory, INSERM, INRA, INSA Lyon, Université Claude Bernard Lyon 1, 69550 Bron, France; Hospices Civils de Lyon, Groupement Hospitalier EST, Département de Cardiologie, IHU-OPERA Bâtiment B13, 69550 Bron, France.
7
Unidad de Química Orgánica y Farmacéutica, Departamento de Química en Ciencias Farmacéuticas, Facultad de Farmacia, Universidad Complutense, 28040 Madrid, Spain.
8
Laboratoire de Physique des Lasers, Atomes et Molécules, Equipe Biophotonique Cellulaire Fonctionnelle, UMR 8523, Parc scientifique de la Haute Borne, Villeneuve d'Ascq, France.
9
Univ Lille, Inserm U1003, PHYCEL Laboratory, Physiologie Cellulaire, F-59000 Lille, France. Electronic address: Natalia.Prevarskaya@univ-lille1.fr.

Abstract

Calcium (Ca2+) release from the endoplasmic reticulum plays an important role in many cell-fate defining cellular processes. Traditionally, this Ca2+ release was associated with the ER Ca2+ release channels, inositol 1,4,5‑triphosphate receptor (IP3R) 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 Ca2+ 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 Ca2+ 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 Ca2+ concentration ([Ca2+]) in mitochondria and the ER. Thus, our study identifies 4TM-TRPM8 isoforms as ER Ca2+ release mechanism distinct from classical Ca2+ release channels.

KEYWORDS:

Alternate transcription; ER calcium fluxes; MAMs; Mitochondria; Prostate cancer; TRP channel

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