Adrenocorticotropin/alpha-melanocyte-stimulating hormone (ACTH/MSH)-like peptides modulate adenylate cyclase activity in rat brain slices: evidence for an ACTH/MSH receptor-coupled mechanism.
The regulation of adenylate cyclase activity by adrenocorticotropin/alpha-melanocyte-stimulating hormone (ACTH/MSH)-like peptides was investigated in rat brain slices using a superfusion method. Adenylate cyclase activity was concentration-dependently increased by ACTH-(1-24), alpha-MSH (EC50 values 16 and 6 nM, respectively), and [Nle4,D-Phe7]alpha-MSH (EC50 value 1.6 nM), in the presence of forskolin (1 microM, optimal concentration). 1-9-Dideoxyforskolin did not augment the response of adenylate cyclase to ACTH-(1-24). Various peptide fragments were tested for their ability to enhance [3H]cyclic AMP production. [Nle4,D-Phe7]alpha-MSH increased [3H]cyclic AMP formation with a maximal effect of 30% and was more potent than ACTH-(1-24), ACTH-(1-16)-NH2, alpha-MSH, ACTH-(1-13)-NH2, [MetO4]alpha-MSH, [MetO2(4),D-Lys8,Phe9]ACTH-(4-9), ACTH-(7-16)-NH2, ACTH-(1-10), and ACTH-(11-24), in order of potency. This structure-activity relationship resembles that found for the previously described peptide-induced display of excessive grooming. ACTH-(1-24) stimulated adenylate cyclase activity in both striatal (maximal effect, approximately 20%) and septal slices (maximal effect, approximately 40%), but not in hippocampal or cortical slices. Lesioning of the dopaminergic projections to the striatum did not result in a diminished effect of [Nle4,D-Phe7]alpha-MSH on [3H]cyclic AMP accumulation, which indicates that the ACTH/MSH receptor-stimulated adenylate cyclase is not located on striatal dopaminergic terminals. ACTH-(1-24) did not affect the dopamine D1 or D2 receptor-mediated modulation of adenylate cyclase activity.(ABSTRACT TRUNCATED AT 250 WORDS)
Department of Pharmacology, Rudolf Magnus Institute, Medical Faculty, University of Utrecht, The Netherlands.
W J
WJ
Florijn
A H
AH
Mulder
D H
DH
Versteeg
W H
WH
Gispen
D015647:2,3,4,5-Tetrahydro-7,8-dihydroxy-1-phenyl-1H-3-benzazepine / Q000494:pharmacology; D015102:3,4-Dihydroxyphenylacetic Acid / Q000378:metabolism; D000262:Adenylyl Cyclases / Q000378:metabolism*; D000324:Adrenocorticotropic Hormone / Q000031:analogs & derivatives* / Q000494:pharmacology*; D000818:Animals; D001921:Brain / Q000187:drug effects / Q000201:enzymology* / Q000378:metabolism; D002851:Chromatography, High Pressure Liquid; D005576:Colforsin / Q000031:analogs & derivatives / Q000494:pharmacology; D000242:Cyclic AMP / Q000378:metabolism; D003891:Desipramine / Q000494:pharmacology; D004298:Dopamine / Q000378:metabolism / Q000494:pharmacology; D004305:Dose-Response Relationship, Drug; D004873:Ergolines / Q000494:pharmacology; D066298:In Vitro Techniques; D007700:Kinetics; D008297:Male; D009928:Organ Specificity; D016627:Oxidopamine / Q000633:toxicity; D019257:Quinpirole; D051381:Rats; D017208:Rats, Wistar; D018043:Receptors, Corticotropin; D011979:Receptors, Pituitary Hormone / Q000187:drug effects / Q000502:physiology*; D013469:Sulpiride / Q000494:pharmacology; D000521:alpha-MSH / Q000494:pharmacology*
D004873:Ergolines; D018043:Receptors, Corticotropin; D011979:Receptors, Pituitary Hormone; D015102:3,4-Dihydroxyphenylacetic Acid; D005576:Colforsin; D019257:Quinpirole; D000521:alpha-MSH; D015647:2,3,4,5-Tetrahydro-7,8-dihydroxy-1-phenyl-1H-3-benzazepine; D013469:Sulpiride; C029446:MSH receptor; D016627:Oxidopamine; D000324:Adrenocorticotropic Hormone; D000242:Cyclic AMP; D000262:Adenylyl Cyclases; D003891:Desipramine; D004298:Dopamine