title: Adrenocorticotropin, vasoactive intestinal polypeptide, growth hormone-releasing factor, and dynorphin compete for common receptors in brain and adrenal.
abstract: 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.
authors.affiliation: Faculty of Medicine, Department of Pharmacology and Therapeutics, University of Manitoba, Winnipeg, Canada.
authors.forename: Z G
authors.initials: ZG
authors.lastname: Li
authors.forename: G
authors.initials: G
authors.lastname: Queen
authors.forename: F S
authors.initials: FS
authors.lastname: LaBella
mesh_terms: D000311:Adrenal Glands / Q000378:metabolism*; D000324:Adrenocorticotropic Hormone / Q000378:metabolism*; D000818:Animals; D001921:Brain / Q000378:metabolism*; D004305:Dose-Response Relationship, Drug; D004399:Dynorphins / Q000378:metabolism; D013007:Growth Hormone-Releasing Hormone / Q000378:metabolism; D008297:Male; D010446:Peptide Fragments / Q000378:metabolism; D010455:Peptides / Q000378:metabolism*; D051381:Rats; D011919:Rats, Inbred Strains; D018043:Receptors, Corticotropin; D011979:Receptors, Pituitary Hormone / Q000378:metabolism*; D013256:Steroids / Q000096:biosynthesis; D014660:Vasoactive Intestinal Peptide / Q000378:metabolism
chemical_list: D010446:Peptide Fragments; D010455:Peptides; D018043:Receptors, Corticotropin; D011979:Receptors, Pituitary Hormone; D013256:Steroids; D014660:Vasoactive Intestinal Peptide; D004399:Dynorphins; D000324:Adrenocorticotropic Hormone; D013007:Growth Hormone-Releasing Hormone