Copyright © 2006, European Society of Cardiology
Functional β-adrenergic receptor signalling on nuclear membranes in adult rat and mouse ventricular cardiomyocytes
aCentre de recherche, Institut de Cardiologie de Montréal, Canada
bDépartement de biochimie et Groupe de recherche universitaire sur les medicaments, Université de Montréal, Canada
cDepartment of Pharmacology and Therapeutics, McGill University, Canada
dDépartement de médecine, Université de Montréal, Canada
* Corresponding author. Department of Pharmacology and Therapeutics, Faculty of Medicine, 13th floor, Room 1303, McIntyre Medical Sciences Building, 3655 Promenade Sir William Osler, Montreal, QC, H3G 1Y6, Canada. Tel.: +1 514 398 1398; fax: +1 514 398 6690. Email address: terence.hebert{at}mcgill.ca
Objective We sought to determine if different β-adrenergic receptor (βAR) subtypes, and their associated signalling machinery, are functionally localized to nuclear membranes.
Methods Employing enriched nuclear preparations, we assayed the specific presence of βAR by measuring 125I-cyanopindolol (CYP) binding, Western blotting, confocal microscopy and functional assays.
Results Western blots of rat heart nuclear fractions and confocal immunofluorescent analysis of adult rat and mouse ventricular cardiomyocytes displayed the presence of β1AR and β3AR but, surprisingly, not the β2AR on nuclear membranes. Nuclear localization of downstream signalling partners Gs, Gi and adenylyl cyclases II and V/VI was also demonstrated. The functional relevance of nuclear βAR was shown by receptor-mediated stimulation of adenylyl cyclase activity by isoproterenol but not the β3AR-selective agonist CL 316243 in enriched nuclear preparations. We also examined the effect of subtype-selective ligands on the initiation of RNA synthesis in isolated nuclei. Both isoproterenol and another β3AR-selective agonist, BRL 37344, increased RNA synthesis which was inhibited by pertussis toxin (PTX). Neither a β1AR-selective agonist, xamoterol, nor a β2AR-selective agonist, procaterol, was able to stimulate transcription. However, both CGP 20712A and ICI 118,551 blocked isoproterenol-mediated effects to varying extents. PTX treatment also revealed that nuclear βAR may be coupled to other signalling pathways in addition to Gi, as stimulation under these conditions reduced initiation of transcription below basal levels.
Conclusion These results highlight differential subcellular localization for βAR subtypes and indicate that βAR may have specific roles in regulating nuclear function in cardiomyocytes.
KEYWORDS Signalling; Nuclear GPCRs; Cardiac function; Adrenergic receptors; G proteins
Time for primary review 24 days
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