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Article

Novel Purine Derivative ITH15004 Facilitates Exocytosis through a Mitochondrial Calcium-Mediated Mechanism

1
Instituto Teófilo Hernando and Departamento de Farmacología y Terapéutica, Universidad Autónoma de Madrid, C/Arzobispo Morcillo, 4, 28029 Madrid, Spain
2
Instituto de Investigación Sanitaria, Hospital Universitario de la Princesa, C/Diego de León, 62, 28006 Madrid, Spain
3
Institut des Biomolécules Max Mousseron (IBMM—UMR5247, CNRS), 1919 Route de Mende, CEDEX 5, 34293 Montpellier, France
4
Departamento de Ciencias Básicas de la Salud, Campus de Alcorcon, Universidad Rey Juan Carlos, Avda. Atenas s/n, 28922 Alcorcón, Spain
5
Fundación Teófilo Hernando, Parque Científico de Madrid, Campus de Cantoblanco, 28049 Madrid, Spain
*
Author to whom correspondence should be addressed.
Academic Editor: Nadège Bellance
Int. J. Mol. Sci. 2022, 23(1), 440; https://doi.org/10.3390/ijms23010440
Received: 6 December 2021 / Revised: 26 December 2021 / Accepted: 29 December 2021 / Published: 31 December 2021
(This article belongs to the Special Issue Mitochondria and Energy Metabolism in Rare Diseases)
Upon depolarization of chromaffin cells (CCs), a prompt release of catecholamines occurs. This event is triggered by a subplasmalemmal high-Ca2+ microdomain (HCMD) generated by Ca2+ entry through nearby voltage-activated calcium channels. HCMD is efficiently cleared by local mitochondria that avidly take up Ca2+ through their uniporter (MICU), then released back to the cytosol through mitochondrial Na+/Ca2+ exchanger (MNCX). We found that newly synthesized derivative ITH15004 facilitated the release of catecholamines triggered from high K+-depolarized bovine CCs. Such effect seemed to be due to regulation of mitochondrial Ca2+ circulation because: (i) FCCP-potentiated secretory responses decay was prevented by ITH15004; (ii) combination of FCCP and ITH15004 exerted additive secretion potentiation; (iii) such additive potentiation was dissipated by the MICU blocker ruthenium red (RR) or the MNCX blocker CGP37157 (CGP); (iv) combination of FCCP and ITH15004 produced both additive augmentation of cytosolic Ca2+ concentrations ([Ca2+]c) K+-challenged BCCs, and (v) non-inactivated [Ca2+]c transient when exposed to RR or CGP. On pharmacological grounds, data suggest that ITH15004 facilitates exocytosis by acting on mitochondria-controlled Ca2+ handling during K+ depolarization. These observations clearly show that ITH15004 is a novel pharmacological tool to study the role of mitochondria in the regulation of the bioenergetics and exocytosis in excitable cells. View Full-Text
Keywords: mitochondria; ITH15004; chromaffin cell; catecholamine release; calcium signalling; neurodegeneration mitochondria; ITH15004; chromaffin cell; catecholamine release; calcium signalling; neurodegeneration
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MDPI and ACS Style

de Pascual, R.; Calzaferri, F.; Gonzalo, P.C.; Serrano-Nieto, R.; de los Ríos, C.; García, A.G.; Gandía, L. Novel Purine Derivative ITH15004 Facilitates Exocytosis through a Mitochondrial Calcium-Mediated Mechanism. Int. J. Mol. Sci. 2022, 23, 440. https://doi.org/10.3390/ijms23010440

AMA Style

de Pascual R, Calzaferri F, Gonzalo PC, Serrano-Nieto R, de los Ríos C, García AG, Gandía L. Novel Purine Derivative ITH15004 Facilitates Exocytosis through a Mitochondrial Calcium-Mediated Mechanism. International Journal of Molecular Sciences. 2022; 23(1):440. https://doi.org/10.3390/ijms23010440

Chicago/Turabian Style

de Pascual, Ricardo, Francesco Calzaferri, Paula C. Gonzalo, Rubén Serrano-Nieto, Cristóbal de los Ríos, Antonio G. García, and Luis Gandía. 2022. "Novel Purine Derivative ITH15004 Facilitates Exocytosis through a Mitochondrial Calcium-Mediated Mechanism" International Journal of Molecular Sciences 23, no. 1: 440. https://doi.org/10.3390/ijms23010440

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