Plasma membrane-associated nucleoside diphosphate kinase (nm23) in the heart is regulated by beta-adrenergic signaling.
1. 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. 2. Among 22 consecutive patients with chronic heart failure who underwent cardiac transplantation, those treated with a beta-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 beta-blocker therapy (n=14). 3. 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 (GDPbetaS). 4. We further tested whether treatment with a beta-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 beta-blocker propranolol prevented both effects. When hypertrophy was induced with thyroid hormone, NDPK did not increase. 5. In conclusion, chronic activation of beta-adrenergic receptors increases the binding of NDPK to cardiac sarcolemma, where it may activate heterotrimeric G proteins.
Lutz
Susanne
S
Klinikum der Universität Heidelberg, Innere Medizin III, Bergheimer Str 58, Heidelberg D-69115, Germany.
Mura
Roman A
RA
Hippe
Hans Joerg
HJ
Tiefenbacher
Christiane
C
Niroomand
Feraydoon
F
D000262:Adenylyl Cyclases / Q000378:metabolism; D000318:Adrenergic beta-Agonists / Q000494:pharmacology; D000319:Adrenergic beta-Antagonists / Q000494:pharmacology* / Q000627:therapeutic use; D000328:Adult; D000368:Aged; D000818:Animals; D006332:Cardiomegaly / Q000139:chemically induced / Q000378:metabolism; D002311:Cardiomyopathy, Dilated / Q000188:drug therapy; D006330:Heart Defects, Congenital / Q000188:drug therapy; D006801:Humans; D007545:Isoproterenol / Q000494:pharmacology; D008297:Male; D008875:Middle Aged; D008954:Models, Biological; D009206:Myocardium / Q000201:enzymology* / Q000473:pathology; D009701:Nucleoside-Diphosphate Kinase / Q000378:metabolism*; D051381:Rats; D017208:Rats, Wistar; D011943:Receptors, Adrenergic, beta / Q000187:drug effects / Q000378:metabolism; D012508:Sarcolemma / Q000187:drug effects* / Q000201:enzymology; D013963:Thyroid Hormones / Q000494:pharmacology; D013997:Time Factors
D000318:Adrenergic beta-Agonists; D000319:Adrenergic beta-Antagonists; D011943:Receptors, Adrenergic, beta; D013963:Thyroid Hormones; D009701:Nucleoside-Diphosphate Kinase; D000262:Adenylyl Cyclases; D007545:Isoproterenol