Novel Purine Derivative ITH15004 Facilitates Exocytosis through a Mitochondrial Calcium-Mediated Mechanism - Archive ouverte HAL Accéder directement au contenu
Article Dans Une Revue International Journal of Molecular Sciences Année : 2022

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

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Upon depolarization of chromaffin cells (CCs), a prompt release of catecholamines occurs. This event is triggered by a subplasmalemmal high-Ca$^2$$^+$ microdomain (HCMD) generated by Ca$^2$$^+$ entry through nearby voltage-activated calcium channels. HCMD is efficiently cleared by local mitochondria that avidly take up Ca$^2$$^+$ through their uniporter (MICU), then released back to the cytosol through mitochondrial Na+/Ca$^2$$^+$ 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 Ca$^2$$^+$ circulation because: (i) FCCP-potentiated secretory responses decay was prevented by ITH15004; (ii) combination of FCCP and ITH15004 exerted additive secretion potentiation; (iii) such additive potentiation was dissipated by the MICU blocker ruthenium red (RR) or the MNCX blocker CGP37157 (CGP); (iv) combination of FCCP and ITH15004 produced both additive augmentation of cytosolic Ca$^2$$^+$ concentrations ([Ca$^2$$^+$]$_c$) K$^+$-challenged BCCs, and (v) non-inactivated [Ca$^2$$^+$]$_c$ transient when exposed to RR or CGP. On pharmacological grounds, data suggest that ITH15004 facilitates exocytosis by acting on mitochondria-controlled Ca$^2$$^+$ 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.
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hal-04567583 , version 1 (03-05-2024)

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Ricardo de Pascual, Francesco Calzaferri, Paula Gonzalo, Rubén Serrano-Nieto, Cristóbal de los Ríos, et al.. Novel Purine Derivative ITH15004 Facilitates Exocytosis through a Mitochondrial Calcium-Mediated Mechanism. International Journal of Molecular Sciences, 2022, 23 (1), pp.440. ⟨10.3390/ijms23010440⟩. ⟨hal-04567583⟩
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