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(Circulation Research. 2007;100:1191.)
© 2007 American Heart Association, Inc.

Cellular Biology

Regulation of Cardiac cAMP Synthesis and Contractility by Nucleoside Diphosphate Kinase B/G Protein ß Dimer Complexes

Hans-Joerg Hippe, Mark Luedde, Susanne Lutz, Henrike Koehler, Thomas Eschenhagen, Norbert Frey, Hugo A. Katus, Thomas Wieland^*, Feraydoon Niroomand^*

From the Innere Medizin III – Kardiologie (H.-J.H., M.L., H.K., N.F., H.A.K., F.N.), Universität Heidelberg, Heidelberg, Germany, Institut für Experimentelle und Klinische Pharmakologie und Toxikologie (S.L., T.W.), Universität Heidelberg, Mannheim, Germany, ^¶Institut für Experimentelle und Klinische Pharmakologie und Toxikologie (T.E.), Universität Hamburg, Hamburg, Germany.

Correspondence to Hans-Joerg Hippe, M.D., Innere Medizin III – Kardiologie, Universität Heidelberg, INF 410, D-69120 Heidelberg, Germany. E-mail hans-joerg.hippe{at}med.uni-heidelberg.de

Heterotrimeric G proteins are pivotal regulators of myocardial contractility. In addition to the receptor-induced GDP/GTP exchange, G protein subunits can be activated by a phosphate transfer via a plasma membrane-associated complex of nucleoside diphosphate kinase B (NDPK B) and G protein ß-dimers (Gß). To investigate the physiological role of this phosphate transfer in cardiomyocytes, we generated a Gß₁₂-dimer carrying a single amino acid exchange at the intermediately phosphorylated His-266 in the ß₁ subunit (Gß₁H266L₂). Recombinantly expressed Gß₁H266L₂ were integrated into heterotrimeric G proteins in rat cardiomyocytes but were deficient in intermediate Gß phosphorylation. Compared with wild-type Gß₁₂ (Gß₁WT₂), overexpression of Gß₁H266L₂ suppressed basal cAMP formation up to 55%. A similar decrease in basal cAMP production occurred when the formation of NDPK B/Gß complexes was attenuated by siRNA-mediated NDPK B knockdown. In adult rat cardiomyocytes expressing Gß₁H266L₂, the basal contractility was suppressed by 50% which correlated to similarly reduced basal cAMP levels and reduced Ser16-phosphorylation of phospholamban. In the presence of the ß-adrenoceptor agonist isoproterenol, the total cAMP formation and contractility were significantly lower in Gß₁H266L₂ than in Gß₁WT₂ expressing cardiomyocytes. However, the relative isoproterenol-induced increased was not affected by Gß₁H266L₂. We conclude that the receptor-independent activation of G proteins via NDPK B/Gß complexes requires the intermediate phosphorylation of G protein ß subunits at His-266. Our results highlight the histidine kinase activity of NDPK B for Gß and demonstrate its contribution to the receptor-independent regulation of cAMP synthesis and contractility in intact cardiomyocytes.

Key Words: G proteins • NDPK • cardiomyocytes • cAMP • contractility

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