Plasma membrane‐associated nucleoside diphosphate kinase (nm23) in the heart is regulated by β‐adrenergic signaling

A receptor‐independent activation of heterotrimeric G proteins by plasma membrane‐associated nucleoside diphosphate kinase (NDPK) has been demonstrated in vivo, and elevated levels of NDPK were found in purified sarcolemmal membranes of patients with end‐stage heart failure. Among 22 consecutive patients with chronic heart failure who underwent cardiac transplantation, those treated with a β‐blocker (n=8) had a 65% lower NDPK content and activity in the cardiac sarcolemma, compared to patients with similar base line characteristics who had no β‐blocker therapy (n=14). The lower NDPK was associated with a reduced NDPK‐dependent, Gi‐mediated inhibition of adenylyl cyclase activity, as assessed by in vitro measurement of adenylyl cyclase activity in the presence of GDP or its kinase‐resistant analog guanosine 5′‐O‐(2‐thio)diphosphate (GDPβS). We further tested whether treatment with a β‐adrenergic agonist would induce an increase in sarcolemmal NDPK. Rats treated with isoproterenol developed myocardial hypertrophy, and NDPK in the sarcolemma rose by 60% during 14 days of treatment. The β‐blocker propranolol prevented both effects. When hypertrophy was induced with thyroid hormone, NDPK did not increase. In conclusion, chronic activation of β‐adrenergic receptors increases the binding of NDPK to cardiac sarcolemma, where it may activate heterotrimeric G proteins. British Journal of Pharmacology (2003) 140, 1019–1026. doi:10.1038/sj.bjp.0705527