Decreased Stimulatory Guanosine Triphosphate Binding Protein

Alterations in the level and function of the stimulatory guanyl nucleotide binding protein (GJ) from the cardiac sarcolemma were examined in a canine model of heart failure. The present study is based on our previous investigations that demonstrated both a loss of /3-adrenergic agonist high-affinity binding sites and a decreased adenylate cyclase activity in sarcolemma from failing hearts. Using cholera toxin and [32PJNAD, we labeled the alpha subunit of G. (G,,) and found a 59% reduction in the level of this protein. Further, a 50% reduction in G, activity was noted in a reconstitution assay utilizing membranes from the mouse S49 lymphoma cell line cyc-, which is deficient in G,. These data suggest that, in this model of pressure-overload left ventricular failure, the acquired defect in the,8-adrenergic receptor/adenylate cyclase system involves a deficiency in the coupling protein G,. Such an abnormality may explain the decreased adrenergic responsiveness of the failing left ventricle.