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.
Nukina
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Department of Pharmacology and Therapeutics, Faculty of Medicine, University of Manitoba, Winnipeg, Canada.
LaBella
F S
FS
D000318:Adrenergic beta-Agonists / Q000378:metabolism*; D000324:Adrenocorticotropic Hormone / Q000494:pharmacology; D000818:Animals; D001667:Binding, Competitive / Q000187:drug effects; D001921:Brain / Q000187:drug effects* / Q000378:metabolism; D004082:Dihydroalprenolol; D004533:Egtazic Acid / Q000494:pharmacology; D066298:In Vitro Techniques; D007545:Isoproterenol / Q000378:metabolism; D008297:Male; D009479:Neuropeptides / Q000494:pharmacology*; D051381:Rats; D011943:Receptors, Adrenergic, beta / Q000187:drug effects* / Q000378:metabolism
D000318:Adrenergic beta-Agonists; D009479:Neuropeptides; D011943:Receptors, Adrenergic, beta; D004533:Egtazic Acid; D004082:Dihydroalprenolol; D000324:Adrenocorticotropic Hormone; D007545:Isoproterenol