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

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, alteration s in gene expression and addition of sarcomeres. These responses enhance ca rdiomyocyte contractile function and thus allow the heart to compensate for increased stress. The hypertrophic effects of NE are mediated through Gq-c oupled alpha (1)-adrenergic receptors and are mimicked by the actions of ot her neurohormones (endothelin, prostaglandin F-2 alpha angiotensin II) that also act on Gq-coupled receptors, Activation of phospholipase C by Gq is n ecessary for these responses, and protein kinase C and MAP kinases have als o been implicated. Gq stimulated cardiac hypertrophy is also evident in tra nsgenic mouse models. In contrast, stimulation of G(s)-coupled beta -adrene rgic receptors or G(i)-coupled receptors do not directly effect cardiomyocy te hypertrophy, Apoptosis is also induced by G-protein-coupled receptor sti mulation 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 fu nction in the failing heart, Cardiomyocytes provide an ideal model system f or understanding the basis for G-protein mediated hypertrophy and apoptosis , and the mechanisms responsible for the transition from compensatory to de leterious levels of signaling. This information may prove critical for desi gning interventions that prevent the pathophysiological consequences of hea rt failure.