Human Myocardial b₁ 389 Arg/Arg Adrenergic Receptors Exhibit a Propensity for Constitutively Active, High Affinity Agonist Binding and Are Selectively Inactivated by Bucindolol

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b₁-adrenergic (b₁ AR) and many other receptors exist in two activation states: active (“R*”) and inactive (“R_i”). R* are detected by high affinity binding to agonists, plus conversion of R* to R_i by GTP or its nonhydrolyzable analogues. R* receptors may also be inactivated to the R_i state by certain receptor ligands with “inverse agonist” properties, whereas agonists function to convert R_i to R*. In human left ventricular membranes that were >75% b₁ (n=12) we determined the degree of R* and R_i in the codon 389 Arg/Arg or Gly/Gly genotype, by performing computer modeling of ^[125]ICYP-(S) norepinephrine competition curves. The R* state was confirmed by conversion of two-site fits to one site by 30 uM Gpp(NH)p. In addition, in preparations of isolated human failing right ventricle (n=41) b₁ AR 389 Arg/Arg receptors were compared to Gly carriers by determining the inverse agonist properties of the b₁-AR antagonists bucindolol, carvedilol, metoprolol and the partial b₁-agonist xamoterol, using the readout of systolic function in the presence of forskolin to augment signal transduction. Results: In b₁ AR 389 Arg/Arg receptors 42.0±21.8% were in the R* state, compared to 11.6±16.4% for Gly/Gly (p=0.025). In isolated human heart preparations genotyped as b₁ AR 389 Arg/Arg bucindolol was an inverse agonist (p=0.0008), whereas metoprolol and carvedilol were neutral antagonists and xamoterol was an agonist. In b₁ AR 389 Gly receptors bucindolol, metoprolol, carvedilol and xamoterol were all neutral antagonists. Conclusions: These data provide a molecular mechanism for bucindolol's novel enhancement of efficacy in patients who have the b₁ AR 389 Arg/Arg genotype, which is selective activation of the large number of R* in this high functioning receptor variant.