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

International Journal of Molecular Sciences

Antonio G. García¹  Ricardo de Pascual¹  Francesco Calzaferri¹  Luis Gandía¹  Paula C. Gonzalo¹  Rubén Serrano-Nieto¹  Cristóbal de los Ríos¹ 

[1] Instituto Teófilo Hernando and Departamento de Farmacología y Terapéutica, Universidad Autónoma de Madrid, C/Arzobispo Morcillo, 4, 28029 Madrid, Spain;

关键词: mitochondria;    ITH15004;    chromaffin cell;    catecholamine release;    calcium signalling;    neurodegeneration;   

DOI  :  10.3390/ijms23010440

来源: DOAJ

【 摘 要 】

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.

【 授权许可】

Unknown