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

Autor:	Ricardo de Pascual, Francesco Calzaferri, Paula C. Gonzalo, Rubén Serrano-Nieto, Cristóbal de los Ríos, Antonio G. García, Luis Gandía
Jazyk:	angličtina
Rok vydání:	2021
Předmět:	calcium signalling QH301-705.5 Chromaffin Cells Primary Cell Culture Catalysis Article Exocytosis Inorganic Chemistry Catecholamines TheoryofComputation_ANALYSISOFALGORITHMSANDPROBLEMCOMPLEXITY catecholamine release chromaffin cell Animals Calcium Signaling Biology (General) Physical and Theoretical Chemistry QD1-999 Molecular Biology Spectroscopy Cells Cultured Organic Chemistry ITH15004 neurodegeneration General Medicine Computer Science Applications Mitochondria Chemistry Calcium Cattle mitochondria
Zdroj:	International Journal of Molecular Sciences; Volume 23; Issue 1; Pages: 440 International Journal of Molecular Sciences International Journal of Molecular Sciences, Vol 23, Iss 440, p 440 (2022)
ISSN:	1422-0067
DOI:	10.3390/ijms23010440
Popis:	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.
Databáze:	OpenAIRE
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