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

Abstract

1 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. 2 Among 22 consecutive patients with chronic heart failure who underwent cardiac transplantation, those treated with a b-blocker (n ¼ 8) had a 65% lower NDPK content and activity in the cardiac sarcolemma, compared to patients with similar base line characteristics who had no b-blocker therapy (n ¼ 14). 3 The lower NDPK was associated with a reduced NDPK-dependent, G i -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 0 -O-(2-thio)diphosphate (GDPbS). 4 We further tested whether treatment with a b-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 b-blocker propranolol prevented both effects. When hypertrophy was induced with thyroid hormone, NDPK did not increase. 5 In conclusion, chronic activation of b-adrenergic receptors increases the binding of NDPK to cardiac sarcolemma, where it may activate heterotrimeric G proteins.

G Proteins

“…In agreement with these data, the progression of cardiac hypertrophy induced by chronic ␤-adrenergic receptor stimulation was paralleled by the increase in membrane-associated NDPK. 17 Consistent with recent reports showing NDPK translocation by stimulation of GPCRs, 20,21 these data suggest that sustained stimulation of ␤-adrenergic receptors increases association of NDPK with the plasma membrane. It is tempting to speculate, that this leads to enhanced formation of basal cAMP and thereby contributes to progression of the disease.…”

“…17 Although total NDPK-levels appear to be unchanged, there is a relative enrichment of NDPK in the membrane fraction of failing myocardium. The mechanism underlying this translocation of NDPK is still unknown.…”

“…Some recent publications indicate that intracellular translocation and complex formations may play an important role. 13,17 Taking into account that the intermediately phosphorylated histidine residues on G␤ but not those on NDPK B are substrates for a recently identified phosphohistidine phosphatase, 18 it will be interesting to see, whether the nucleotide kinase and the histidine kinase functions are subject to individual regulation. Similarly, the downstream effectors of NDPKs, that have been identified likely represent only a small fraction of the entire picture (Figure).…”

The actions of NME1/NDPK-A and NME2/NDPK-B as protein kinases

“…It has also been observed that in plasma membranes of hearts from patients with severe congestive heart failure, but not in patients treated with a βAR antagonist, a threefold elevated content and activity of NDPK is detected and that chronic treatment of rats with isoproterenol, induces an increase in plasma membrane-bound NDPK-B. 66,67 This suggests that NDPK-B membrane content may be under the control of β-adrenergic signaling and that NDPK may have an important role in heart failure and hypertrophy. Abu-Taha et al 68 show that NDPK-C-mediates targeting of NDPK-A and -B isoforms to the plasma membrane and formation of the NDPK-B/G proteins complex in cardiomyocytes and is thus a critical regulator of β-adrenoceptor/cAMP signaling and cardiac contractility.…”

Regulation of heterotrimeric G-protein signaling by NDPK/NME proteins and caveolins: an update

“…50,51 Indeed, both patients and isoprenaline-stimulated rats treated with β-blockers showed a reduced NDPK content at the plasma membrane. 52 The increased NDPK expression in heart failure and the stimulatory effect of NDPKs on cAMP and contractility in animal models appear at odds with the decreased cAMP levels and impaired contractility in heart failure. However, it has been suggested that NDPKs may also enhance G i signaling in patients, contributing to a switch from NDPK-mediated regulation of G s to G i in heart failure, which might contribute to the decreased cAMP and impaired contractility (Figure 3).…”