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Tetrabenazine Facilitates Exocytosis by Enhancing Calcium-Induced Calcium Release through Ryanodine Receptors

Publicated to:JOURNAL OF PHARMACOLOGY AND EXPERIMENTAL THERAPEUTICS. 371 (1): 219-230 - 2019-01-01 371(1), DOI: 10.1124/jpet.119.256560

Authors: De Pascual R; Álvarez-Ortego N; De Los Ríos C; Jacob-Mazariego G; García A

Affiliations

Hosp Univ Princesa, Dept Farmacol & Terapeut, Madrid, Spain - Author
Hosp Univ Princesa, Inst Invest Sanitaria, Madrid, Spain - Author
Hospital Universitario de la Princesa - Author
Inst Teofilo Hernando, Madrid, Spain - Author
Univ Autonoma Madrid, Fac Med, Madrid, Spain - Author
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Abstract

Copyright © 2019 by The American Society for Pharmacology and Experimental Therapeutics. Vesicular monoamine transporter-2 is expressed in the presynaptic secretory vesicles membrane in the brain. Its blockade by tetrabenazine (TBZ) causes depletion of dopamine at striatal basal ganglia; this is the mechanism underlying its long-standing use in the treatment of Huntington's disease. In the frame of a project aimed at investigating the kinetics of exocytosis from vesicles with partial emptying of their neurotransmitter, we unexpectedly found that TBZ facilitates exocytosis; thus, we decided to characterize such effect. We used bovine chromaffin cells (BCCs) challenged with repeated pulses of high K+ Upon repeated K+ pulsing, the exocytotic catecholamine release responses were gradually decaying. However, when cells were exposed to TBZ, responses were mildly augmented and decay rate delayed. Facilitation of exocytosis was not due to Ca2+ entry blockade through voltage-activated calcium channels (VACCs) because, in fact, TBZ mildly blocked the whole-cell Ca2+ current. However, TBZ mimicked the facilitatory effects of exocytosis elicited by BayK8644 (L-subtype VACC agonist), an effect blocked by nifedipine (VACC antagonist). On the basis that TBZ augmented the secretory responses to caffeine (but not those of histamine), we monitored its effects on cytosolic Ca2+ elevations ([Ca2+]c) triggered by caffeine or histamine. While the responses to caffeine were augmented twice by TBZ, those of histamine were unaffected; the same happened in rat cortical neurons. Hence, we hypothesize that TBZ facilitates exocytosis by increasing Ca2+ release through the endoplasmic reticulum ryanodine receptor channel (RyR). Confirming this hypothesis are docking results, showing an interaction of TBZ with RyRs. This is consonant with the existence of a healthy Ca2+-induced-Ca2+-release mechanism in BCCs. SIGNIFICANCE STATEMENT: A novel mechanism of action for tetrabenazine (TBZ), a drug used in the therapy of Huntington's disease (HD), is described here. Such mechanism consists of facilitation by combining TBZ with the ryanodine receptor of the endoplasmic reticulum, thereby increasing Ca2+-induced Ca2+ release. This novel mechanism should be taken into account when considering the efficacy and/or safety of TBZ in the treatment of chorea associated with HD and other disorders. Additionally, it could be of interest in the development of novel medicines to treat these pathological conditions.

Keywords
Adrenal chromaffin cellsCa2+ channelsCatecholamine releaseCyclopiazonic acidDifferent patternsHuntingtons-diseaseProtein-kinase-cSarcoplasmic-reticulumSecretionVesicular monoamine transporter

Quality index

Bibliometric impact. Analysis of the contribution and dissemination channel

The work has been published in the journal JOURNAL OF PHARMACOLOGY AND EXPERIMENTAL THERAPEUTICS due to its progression and the good impact it has achieved in recent years, according to the agency Scopus (SJR), it has become a reference in its field. In the year of publication of the work, 2019, it was in position , thus managing to position itself as a Q1 (Primer Cuartil), in the category Pharmacology.

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 2025-05-19:

  • WoS: 3
  • Scopus: 4
  • OpenCitations: 4
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 2025-05-19:

  • The use, from an academic perspective evidenced by the Altmetric agency indicator referring to aggregations made by the personal bibliographic manager Mendeley, gives us a total of: 18.
  • 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: 18 (PlumX).

With a more dissemination-oriented intent and targeting more general audiences, we can observe other more global scores such as:

  • The Total Score from Altmetric: 0.25.
  • The number of mentions on the social network X (formerly Twitter): 1 (Altmetric).

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.
Leadership analysis of institutional authors

There is a significant leadership presence as some of the institution’s authors appear as the first or last signer, detailed as follows: First Author (de Pascual R) and Last Author (GARCIA GARCIA, ANTONIO).

the author responsible for correspondence tasks has been GARCIA GARCIA, ANTONIO.