Endocrinology, Vol 126, 1327-1333, Copyright © 1990 by Endocrine Society

ARTICLES

Adrenocorticotropin, vasoactive intestinal polypeptide, growth hormone- releasing factor, and dynorphin compete for common receptors in brain and adrenal

ZG Li, G Queen and FS LaBella
Faculty of Medicine, Department of Pharmacology and Therapeutics, University of Manitoba, Winnipeg, Canada.

It was previously shown in this laboratory that high affinity binding of [125I]ACTH-(1-24) to membranes from rat brain was inhibited by vasoactive intestinal polypeptide (VIP), GH-releasing factor (GRF), and dynorphin (DYN), but not by other peptides tested. We now show that these peptides compete for [125I]VIP binding in brain and for [125I]ACTH-(1-24) binding in adrenal cortex and promote steroidogenesis. The high affinity sites for [125I]ACTH-(1-24) in the rat brain and bovine adrenal had Kd values of 0.51 +/- 0.41 and 3.9 +/- 1.3 nM, respectively; and the Ki values for VIP were 5.4 +/- 4.2 and 1.4 +/- 0.51 nM, respectively. In rat brain and bovine adrenal the high affinity site for [125I]VIP had Kd values of 2.9 +/- 1.7 and 0.5 +/- 0.8 nM, respectively, and Ki values for ACTH of 23.6 +/- 14.0 and 22.2 +/- 33.0 nM, respectively. In brain, DYN and GRF inhibited binding of [125I]VIP with Ki values of 49 and 30 nM, respectively. Cortisol secretion from isolated bovine adrenal cortical cells was significantly stimulated by 10(-10) M ACTH, VIP, DYN, or GRF, and a maximal response occurred for each at 10(-8) M. However, maximal cortisol production in response to VIP, DYN, or GRF was only about half that by ACTH-(1-24). The combination of ACTH-(1-24) and VIP, each at 10(-10) M, was additive in stimulating cortisol production, whereas each at 10(-8) M caused no greater response than ACTH alone. There was an additive steroidogenic effect of VIP plus ACTH-(1-10), but not VIP plus ACTH-(11-24). Specific binding of [125I]ACTH-(11-24) in adrenal membranes was inhibited by unlabeled ACTH-(11-24), ACTH-(1-24), VIP, GRF, and DYN, but not by ACTH- (1-10), peptide T, TRH, alpha MSH, or beta-endorphin; there was no specific binding of [125I]ACTH-(1-10). Functional studies and binding data, in conjunction with the existence of homologous amino acid sequences, indicate that VIP, GRF, and DYN interact at a subpopulation of ACTH receptors that recognizes a moiety within the 11-24 sequence of the ACTH molecule.

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