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SERCA-1 conformational change exerted by the Ca2+-channel blocker diltiazem affects mammalian skeletal muscle function.
Jiménez-Garduño, Aura; Ramirez-Soto, Ibrahim; Miranda-Rodríguez, Ileana; Gitler, Sofía; Ortega, Alicia.
Afiliação
  • Jiménez-Garduño A; Department of Biochemistry, Facultad de Medicina, School of Medicine, Universidad Nacional Autónoma de México, México City, Mexico; Department of Health Sciences, Universidad de las Américas Puebla, San Andrés Cholula, Puebla, Mexico.
  • Ramirez-Soto I; Department of Biochemistry, Facultad de Medicina, School of Medicine, Universidad Nacional Autónoma de México, México City, Mexico; Department of Kinesiology and Health Sciences, University of Waterloo, Ontario, Canada.
  • Miranda-Rodríguez I; Department of Biochemistry, Facultad de Medicina, School of Medicine, Universidad Nacional Autónoma de México, México City, Mexico.
  • Gitler S; Department of Biochemistry, Facultad de Medicina, School of Medicine, Universidad Nacional Autónoma de México, México City, Mexico; Department of Internal Medicine, ABC Medical Center, Sur 136 166, Las Américas, Alvaro Obregon, 0112, Mexico City.
  • Ortega A; Department of Biochemistry, Facultad de Medicina, School of Medicine, Universidad Nacional Autónoma de México, México City, Mexico. Electronic address: aortega@unam.mx.
Cell Calcium ; 119: 102852, 2024 May.
Article em En | MEDLINE | ID: mdl-38412581
ABSTRACT
In skeletal muscle (SM), inward Ca2+-currents have no apparent role in excitation-contraction coupling (e-c coupling), however the Ca2+-channel blocker can affect twitch and tetanic muscle in mammalian SM. Experiments were conducted to study how diltiazem (DLZ) facilitates e-c coupling and inhibits contraction. 1) In complete Extensor Digitorum Longus (EDL) muscle and single intact fibres, 0.03 mM DLZ causes twitch potentiation and decreases force during tetanic activity, with increased fatigue. 2) In split open fibres isolated from EDL fibres, DLZ inhibits sarcoplasmic reticulum (SR) Ca2+-loading in a dose-dependent manner and has a potentiating effect on caffeine-induced SR Ca2+-release. 3) In isolated light SR (LSR) vesicles, SERCA1 hydrolytic activity is not affected by DLZ up to 0.2 mM. However, ATP-dependent Ca2+-uptake was inhibited in a dose-dependent manner at a concentration where e-c coupling is changed. 4) The passive Ca2+-efflux from LSR was reduced by half with 0.03 mM diltiazem, indicating that SR leaking does not account for the decreased Ca2+-uptake. 5) The denaturation profile of the SERCA Ca2+-binding domain has lower thermal stability in the presence of DLZ in a concentration-dependent manner, having no effect on the nucleotide-binding domain. We conclude that the effect of DLZ on SM is exerted by crossing the sarcolemma and interacting directly with the SERCA Ca2+-binding domain, affecting SR Ca2+-loading during relaxation, which has a consequence on SM contractility. Diltiazem effect on SM could be utilized as a tool to understand SM e-c coupling and muscle fatigue.
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Texto completo: 1 Coleções: 01-internacional Base de dados: MEDLINE Assunto principal: Diltiazem / Músculo Esquelético Limite: Animals Idioma: En Revista: Cell Calcium Ano de publicação: 2024 Tipo de documento: Article País de afiliação: México País de publicação: Holanda
Texto completo
Adicionar na Minha BVS
Imprimir
XML
PubMed Links
Buscar no Google

Texto completo: 1 Coleções: 01-internacional Base de dados: MEDLINE Assunto principal: Diltiazem / Músculo Esquelético Limite: Animals Idioma: En Revista: Cell Calcium Ano de publicação: 2024 Tipo de documento: Article País de afiliação: México País de publicação: Holanda