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De Los Rios, CAuthor

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September 27, 2022
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Novel Purine Derivative ITH15004 Facilitates Exocytosis through a Mitochondrial Calcium-Mediated Mechanism

Publicated to: International Journal Of Molecular Sciences. 23 (1): 440- - 2022-01-01 23(1), DOI: 10.3390/ijms23010440

Authors:

de Pascual, R; Calzaferri, F; Gonzalo, PC; Serrano-Nieto, R; de Los Ríos, C; García, AG; Gandía, L
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Affiliations

CNRS, Inst Biomol Max Mousseron IBMM UMR5247, 1919 Route Mende, F-34293 Montpellier 5, France - Author
Fdn Teofilo Hernando, Parque Cient Madrid,Campus Cantoblanco, Madrid 28049, Spain - Author
Hosp Univ La Princesa, Inst Invest Sanitaria, C Diego de Leon 62, Madrid 28006, Spain - Author
Univ Autonoma Madrid, Dept Farmacol & Terapeut, C Arzobispo Morcillo 4, Madrid 28029, Spain - Author
Univ Autonoma Madrid, Inst Teofilo Hernando, C Arzobispo Morcillo 4, Madrid 28029, Spain - Author
Univ Rey Juan Carlos, Dept Ciencias Basicas Salud, Campus Alcorcon,Avda Atenas S-N, Alcorcon 28922, Spain - Author
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Abstract

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.
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Keywords

4 (2 hydroxyethyl) 1 piperazineethanesulfonic acid7 chloro 5 (2 chlorophenyl) 1,5 dihydro 4,1 benzothiazepin 2(3h) oneAdrenal-medullaAmperometryAnimalAnimalsAntibiotic agentArticleBioenergyBovineBovine serum albuminCa2+CaffeineCalciumCalcium cell levelCalcium ionCalcium signalingCalcium signallingCarbonyl cyanide 4 trifluoromethoxy)phenylhydrazoneCatecholamineCatecholamine releaseCatecholaminesCattleCell cultureCells, culturedCentrifugationChannelsChemical compoundChromaffin cellChromaffin cellsControlled studyCytologyData analysisDepolarizationDimethyl sulfoxideDrug effectElectrophysiologyEndoplasmic-reticulumExocytosisFetal bovine serumFluorescenceGlucoseHumanHuman cellIth15004Magnesium chlorideMetabolismMicroscopyMitochondriaMitochondrionNeurodegenerationNifedipineNonhumanOxidationPatch-clampPhPharmacologyPhysiologyPrimary cell culturePurine derivativeRutheniumRuthenium redRyanodineSeparationSodium calcium exchange proteinSodium hydroxideStimulationThapsigarginTriton x 100Unclassified drugVoltage gated calcium channelWhole cell patch clamp

Quality index

Bibliometric impact. Analysis of the contribution and dissemination channel

The work has been published in the journal International Journal Of Molecular Sciences due to its progression and the good impact it has achieved in recent years, according to the agency WoS (JCR), it has become a reference in its field. In the year of publication of the work, 2022, it was in position 66/285, thus managing to position itself as a Q1 (Primer Cuartil), in the category Biochemistry & Molecular Biology.

Independientemente del impacto esperado determinado por el canal de difusión, es importante destacar el impacto real observado de la propia aportación.

Según las diferentes agencias de indexación, el número de citas acumuladas por esta publicación hasta la fecha 2026-01-01:

  • WoS: 1
  • Scopus: 1
  • Europe PMC: 1
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Impact and social visibility

From the perspective of influence or social adoption, and based on metrics associated with mentions and interactions provided by agencies specializing in calculating the so-called "Alternative or Social Metrics," we can highlight as of 2026-01-01:

  • The use of this contribution in bookmarks, code forks, additions to favorite lists for recurrent reading, as well as general views, indicates that someone is using the publication as a basis for their current work. This may be a notable indicator of future more formal and academic citations. This claim is supported by the result of the "Capture" indicator, which yields a total of: 5 (PlumX).

It is essential to present evidence supporting full alignment with institutional principles and guidelines on Open Science and the Conservation and Dissemination of Intellectual Heritage. A clear example of this is:

  • The work has been submitted to a journal whose editorial policy allows open Open Access publication.
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Leadership analysis of institutional authors

This work has been carried out with international collaboration, specifically with researchers from: France.

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Awards linked to the item

This work was supported by the European Union's Horizon 2020 Research and Innovation Programme under Marie Sklodowska-Curie grant agreement no. 766124 and by Acciones Estrategicas en Salud, Proyectos de Investigacion en Salud (ISCIII/FEDER, PI19/01724). We thank the continued support of Fundacion Teofilo Hernando.
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