Privileged crosstalk between TRPV1 channels and mitochondrial calcium shuttling machinery controls nociception

The nociceptive noxious heat-activated receptor - TRPV1, conducts calcium and sodium, thus producing a depolarizing receptor potential, leading to activation of nociceptive neurons. TRPV1-mediated calcium and sodium influx is negatively modulated by calcium, via calcium-dependent desensitization of...

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Bibliographic Details
Published in:	Biochimica et biophysica acta Vol. 1863; no. 12; pp. 2868 - 2880
Main Authors:	Nita, Iulia I., Caspi, Yaki, Gudes, Sagi, Fishman, Dimitri, Lev, Shaya, Hersfinkel, Michal, Sekler, Israel, Binshtok, Alexander M.
Format:	Journal Article
Language:	English
Published:	Netherlands Elsevier B.V 01-12-2016
Subjects:	Action Potentials - drug effects Action Potentials - physiology Animals Calcium - metabolism Calcium Channels - genetics Calcium Channels - metabolism Capsaicin Capsaicin - pharmacology Egtazic Acid - analogs & derivatives Egtazic Acid - pharmacology Ganglia, Spinal - cytology Ganglia, Spinal - drug effects Ganglia, Spinal - metabolism Gene Expression Regulation HEK293 Cells Humans Male Membrane Potential, Mitochondrial - drug effects Membrane Potential, Mitochondrial - physiology Mitochondrial calcium signaling Molecular Imaging NCLX Nociception Nociceptors - cytology Nociceptors - drug effects Nociceptors - metabolism Pain Primary Cell Culture Rats Rats, Sprague-Dawley RNA, Small Interfering - genetics RNA, Small Interfering - metabolism Single-Cell Analysis Sodium - metabolism Sodium-Calcium Exchanger - antagonists & inhibitors Sodium-Calcium Exchanger - genetics Sodium-Calcium Exchanger - metabolism TRPV Cation Channels - antagonists & inhibitors TRPV Cation Channels - genetics TRPV Cation Channels - metabolism TRPV1 Nociception [Ca2+]C IP3R NCLX Capsaicin FCCP RyR siControlHEK cells TRPV1 siMCU 2-APB shMCU siControl siNCLXHEK cells CCCP Pain AAV CGP37157 Mitochondrial calcium signaling [Ca2+]M DRG MCU siNCLX
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Summary:	The nociceptive noxious heat-activated receptor - TRPV1, conducts calcium and sodium, thus producing a depolarizing receptor potential, leading to activation of nociceptive neurons. TRPV1-mediated calcium and sodium influx is negatively modulated by calcium, via calcium-dependent desensitization of TRPV1 channels. A mitochondrial Ca2+ uniporter - MCU, controls mitochondrial Ca2+ entry while a sodium/calcium transporter - NCLX shapes calcium and sodium transients by mediating sodium entry into and removing calcium from the mitochondria. The functional interplay between TRPV1, MCU and NCLX, in controlling the cytosolic and mitochondrial calcium and sodium transients and subsequently the nociceptive excitability, is poorly understood. Here, we used cytosolic and mitochondrial fluorescent calcium and sodium imaging together with electrophysiological recordings of TRPV1-induced currents in HEK293T cells and nociceptor-like dissociated rat dorsal root ganglion neurons, while modulating NCLX or MCU expression using specific small interfering RNA (siNCLX). We show that the propagation of the TRPV1-induced cytosolic calcium and sodium fluxes into mitochondria is dependent on coordinated activity of NCLX and MCU. Thus, knocking-down of NCLX triggers down regulation of MCU dependent mitochondrial Ca2+ uptake. This in turn decreases rate and amplitude of TRPV1-mediated cytosolic calcium, which inhibits capsaicin-induced inward current and neuronal firing. TRPV1-mediated currents were fully rescued by intracellular inclusion of the fast calcium chelator BAPTA. Finally, NCLX controls capsaicin-induced cell death, by supporting massive mitochondrial Ca2+ shuttling. Altogether, our results suggest that NCLX, by regulating cytosolic and mitochondrial ionic transients, modulates calcium-dependent desensitization of TRPV1 channels, thereby, controlling nociceptive signaling. •In nociceptors TRPV1-mediated Na+ and Ca2+ fluxes propagate into mitochondria.•Mitochondrial MCU and NCLX propagate TRPV1 but not RyR-mediated Ca2+ transients.•Knockdown of the NCLX attenuates TRPV1-induced neuronal firing and cell death.•TRPV1/MCU/NCLX interactions are required for Ca2+-dependent regulation of TRPV1.•Cross-talk between mitochondrial MCU/NCLX and TRPV1 is essential for nociception.
ISSN:	0167-4889 0006-3002 1879-2596
DOI:	10.1016/j.bbamcr.2016.09.009