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Differential Downregulation of ß1-Adrenergic Receptor Signaling in the Heart.
Xu, Bing; Bahriz, Sherif; Salemme, Victoria R; Wang, Ying; Zhu, Chaoqun; Zhao, Meimi; Xiang, Yang K.
Afiliación
  • Xu B; VA Northern California Health Care System Mather CA USA.
  • Bahriz S; Department of Pharmacology University of California at Davis Davis CA USA.
  • Salemme VR; Department of Pharmacology University of California at Davis Davis CA USA.
  • Wang Y; Department of Clinical Pathology, Faculty of Medicine Mansoura University Mansoura Egypt.
  • Zhu C; Department of Pharmacology University of California at Davis Davis CA USA.
  • Zhao M; Department of Pharmacology University of California at Davis Davis CA USA.
  • Xiang YK; Department of Pharmacology, School of Medicine Southern University of Science and Technology Shenzhen China.
J Am Heart Assoc ; 13(12): e033733, 2024 Jun 18.
Article en En | MEDLINE | ID: mdl-38860414
ABSTRACT

BACKGROUND:

Chronic sympathetic stimulation drives desensitization and downregulation of ß1 adrenergic receptor (ß1AR) in heart failure. We aim to explore the differential downregulation subcellular pools of ß1AR signaling in the heart. METHODS AND

RESULTS:

We applied chronic infusion of isoproterenol to induced cardiomyopathy in male C57BL/6J mice. We applied confocal and proximity ligation assay to examine ß1AR association with L-type calcium channel, ryanodine receptor 2, and SERCA2a ((Sarco)endoplasmic reticulum calcium ATPase 2a) and Förster resonance energy transfer-based biosensors to probe subcellular ß1AR-PKA (protein kinase A) signaling in ventricular myocytes. Chronic infusion of isoproterenol led to reduced ß1AR protein levels, receptor association with L-type calcium channel and ryanodine receptor 2 measured by proximity ligation (puncta/cell, 29.65 saline versus 14.17 isoproterenol, P<0.05), and receptor-induced PKA signaling at the plasma membrane (Förster resonance energy transfer, 28.9% saline versus 1.9% isoproterenol, P<0.05) and ryanodine receptor 2 complex (Förster resonance energy transfer, 30.2% saline versus 10.6% isoproterenol, P<0.05). However, the ß1AR association with SERCA2a was enhanced (puncta/cell, 51.4 saline versus 87.5 isoproterenol, P<0.05), and the receptor signal was minimally affected. The isoproterenol-infused hearts displayed decreased PDE4D (phosphodiesterase 4D) and PDE3A and increased PDE2A, PDE4A, and PDE4B protein levels. We observed a reduced role of PDE4 and enhanced roles of PDE2 and PDE3 on the ß1AR-PKA activity at the ryanodine receptor 2 complexes and myocyte shortening. Despite the enhanced ß1AR association with SERCA2a, the endogenous norepinephrine-induced signaling was reduced at the SERCA2a complexes. Inhibiting monoamine oxidase A rescued the norepinephrine-induced PKA signaling at the SERCA2a and myocyte shortening.

CONCLUSIONS:

This study reveals distinct mechanisms for the downregulation of subcellular ß1AR signaling in the heart under chronic adrenergic stimulation.
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Texto completo: 1 Colección: 01-internacional Base de datos: MEDLINE Asunto principal: Transducción de Señal / Regulación hacia Abajo / Receptores Adrenérgicos beta 1 / Proteínas Quinasas Dependientes de AMP Cíclico / Canal Liberador de Calcio Receptor de Rianodina / Canales de Calcio Tipo L / Miocitos Cardíacos / ATPasas Transportadoras de Calcio del Retículo Sarcoplásmico / Isoproterenol / Ratones Endogámicos C57BL Límite: Animals Idioma: En Revista: J Am Heart Assoc Año: 2024 Tipo del documento: Article Pais de publicación: Reino Unido
Texto completo
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Texto completo: 1 Colección: 01-internacional Base de datos: MEDLINE Asunto principal: Transducción de Señal / Regulación hacia Abajo / Receptores Adrenérgicos beta 1 / Proteínas Quinasas Dependientes de AMP Cíclico / Canal Liberador de Calcio Receptor de Rianodina / Canales de Calcio Tipo L / Miocitos Cardíacos / ATPasas Transportadoras de Calcio del Retículo Sarcoplásmico / Isoproterenol / Ratones Endogámicos C57BL Límite: Animals Idioma: En Revista: J Am Heart Assoc Año: 2024 Tipo del documento: Article Pais de publicación: Reino Unido