Neuropeptides modulate beta-adrenergic agonist binding and receptor downregulation in slices of rat brain

Displacement curves of the beta-adrenergic agonist (-)-isoproterenol, on the binding of [3H]-dihydroalprenolol (DHA) in homogenates from the brain of rat defined a two-site model of high (KH; 8.5 +/- 1.6 nM) and low (KL; 771 +/- 111 nM) affinity. The KL/KH ratio was 84.5 +/- 4.5. Somatostatin, ACTH, dynorphin and mastoparan, but not vasoactive intestinal peptide (VIP), substance P, met-enkephalin or leu-enkephalin, each at 1 microM, decreased the KL/KH ratio to 35.2 +/- 4.2, 43.0 +/- 5.0, 52.0 +/- 2.3 and 60.3 +/- 8.0, respectively, without significant effect on either the Kd or Bmax of antagonist binding. Calcium was required for this effect of the neuropeptides. In slices from whole brain of rat, incubated for 2 hr, ACTH attenuated the isoproterenol-induced downregulation of beta-adrenoceptors. For beta-adrenergic agonists, there appeared to be a close correlation between the KL/KH ratio and intrinsic activity. These results suggest that certain neuropeptides may influence beta-adrenergic neurotransmission by modulating the intrinsic activity of beta-agonists. This modulation is manifested, at least in part, by changes in both binding affinity and receptor down-regulation.