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  • Review Article
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Review Article

G-proteins in growth and apoptosis: lessons from the heart

Oncogene volume 20, pages 1626–1634 (2001)Cite this article

Abstract

The acute contractile function of the heart is controlled by the effects of released nonepinephrine (NE) on cardiac adrenergic receptors. NE can also act in a more chronic fashion to induce cardiomyocyte growth, characterized by cell enlargement (hypertrophy), increased protein synthesis, alterations in gene expression and addition of sarcomeres. These responses enhance cardiomyocyte contractile function and thus allow the heart to compensate for increased stress. The hypertrophic effects of NE are mediated through Gq-coupled α1-adrenergic receptors and are mimicked by the actions of other neurohormones (endothelin, prostaglandin F2α angiotensin II) that also act on Gq-coupled receptors. Activation of phospholipase C by Gq is necessary for these responses, and protein kinase C and MAP kinases have also been implicated. Gq stimulated cardiac hypertrophy is also evident in transgenic mouse models. In contrast, stimulation of Gs-coupled β-adrenergic receptors or Gi-coupled receptors do not directly effect cardiomyocyte hypertrophy. Apoptosis is also induced by G-protein-coupled receptor stimulation in cardiomyocytes. Sustained or excessive activation of either Gq- or Gs-signaling pathways results in apoptotic loss of cardiomyocytes both in vitro and in vivo. Apoptosis is associated with decreased ventricular function in the failing heart. Cardiomyocytes provide an ideal model system for understanding the basis for G-protein mediated hypertrophy and apoptosis, and the mechanisms responsible for the transition from compensatory to deleterious levels of signaling. This information may prove critical for designing interventions that prevent the pathophysiological consequences of heart failure.

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Abbreviations

α-AR:

α-AdrR: α-adrenergic receptor

β-AR:

β-AdrR: β-adrenergic receptor

β-ARK:

β-adrenergic receptor kinase

α-MHC:

β-MHC: α-myosin heavy chain, β-myosin heavy chain

ACE::

angiotensin-converting enzyme

ANF:

atrial natriuretic factor

Ang II:

angiotensin II

cAMP:

cyclic AMP

ET-1:

endothelin-1

GAP:

GTPase activator protein

GPCR:

G protein-coupled receptor

ISO:

isoproterenol

LPA:

lysophosphatidic acid

MAP kinase:

mitogen-activated protein kinase

MLC-2:

myosin light chain-2

NE:

norepinephrine

NRVM:

neonatal rat ventricular myocyte

PAR:

protein-activated receptor

PE:

phenylephrine

PGF2α:

prostaglandin F2α

PIP2:

phosphatidylinositol bisphosphate

PKA:

cAMP-dependent protein kinase

PKC:

protein kinase C

PLC:

phospholipase C

RACKS:

receptors for activated C-kinases

RGS4:

regulator of G protein signaling 4

SPC:

sphingosylphosphorylcholine.

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    Present address: Arena Pharmaceuticals, Inc., 6166 Nancy Ridge Drive, San Diego, 92121, CA, USA

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  1. Department of Pharmacology, University of California, San Diego, 9500 Gilman Drive, 0636, La Jolla, CA, California, 92093-0636, USA

    John W Adams & Joan Heller Brown

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Adams, J., Brown, J. G-proteins in growth and apoptosis: lessons from the heart. Oncogene 20, 1626–1634 (2001). https://doi.org/10.1038/sj.onc.1204275

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