© 1999 American Heart Association, Inc.
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The Molecular Basis for Distinct ß-Adrenergic Receptor Subtype Actions in Cardiomyocytes
From the Departments of Pharmacology and Medicine, College of Physicians and Surgeons, Columbia University, New York, NY.
Correspondence to Susan F. Steinberg, MD, Associate Professor of Pharmacology and Medicine, Department of Pharmacology, College of Physicians and Surgeons, Columbia University, 630 West 168th St, New York, NY 10032. E-mail sfs1@columbia.edu
Key Words: ß-adrenergic receptor subtype • cardiomyocyte • cAMP • contractility
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Introduction |
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Catecholamines exert physiologically important effects on the electrical properties and mechanical performance of the heart through the activation of adrenergic receptors. It has been 50 years since Ahlquist1 first postulated that the excitatory and inhibitory pressor responses to catecholamines must be mediated by distinct adrenergic receptors (ARs), then designated
(for excitatory) and ß (for inhibitory).
Ahlquist’s classification was expanded further by Lands et
al,2 who recognized that both - and ß-ARs could be
conveniently categorized into 2 distinct subtypes on the basis of their
relative potencies for ligands available at that time. In the ensuing
years, the predominant AR expressed by cardiomyocytes was
shown to conform to the ß1-AR subtype. Our
understanding of the molecular basis for sympathetic modulation was
advanced further by the observations that under normal
physiological conditions catecholamines
induce positive inotropic, chronotropic, and lusitropic (relaxant)
responses in the heart through a
ß1-AR–activated pathway, which
involves the stimulatory GTP regulatory protein
(Gs), activation of adenylyl cyclase (AC),
accumulation of cAMP, stimulation of cAMP-dependent protein kinase A
(PKA), and phosphorylation of key target proteins
(including the L-type calcium channel
[ICa,L], phospholamban [PLB], and
troponin I [TNI]). Potential contributions of other AR subtypes to
the mechanism(s) of catecholamine action in the heart were
largely ignored in early studies. However, the traditional notion that
only ß1-ARs support cardiac contractile
function has been challenged by recent research demonstrating that
cardiac myocytes also express ß2-ARs that link
to important changes in cardiac contractile function. Although these
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