5-Hydroxytryptamine stimulates corticosteroid-sensitive CRF release from cultured foetal hypothalamic cells. Role of protein kinases.
5-Hydroxytryptamine (5-HT) has been shown to activate the hypothalamo-pituitary-adrenal axis, possibly by a direct action on hypothalamic CRF synthesis and release. In order to study the mechanisms involved in this effect, foetal hypothalamic cells were cultured and corticotropin-releasing factor-41 (CRF) release was measured by radioimmunoassay. 5-HT induced CRF release in a dose-dependent manner. Further studies were performed with a specific protein kinase C inhibitor, H-7 (1-(5-isoquinolinesulfonyl)-2-methyl-piperazine) and a specific cyclic adenosine monophosphate-dependent protein kinase inhibitor, IP-20. Basal release of CRF-41 from the cultured hypothalamic cells was unaffected by IP-20 and was only diminished at a high (50 microM) concentration of H-7. 5-HT stimulated-CRF release, however, was blocked by both H-7 and IP-20. Dexamethasone and aldosterone both caused a dose-dependent inhibition of 5-HT induced CRF release. These results demonstrate that CRF can be released from hypothalamic neurons in response to 5-HT through a protein kinase C and protein kinase A dependent mechanism and that 5-HT stimulated CRF release can be inhibited by dexamethasone and aldosterone.
Hu
S B
SB
Neuroendocrinology Unit, Charing Cross and Westminster Medical School, Charing Cross Hospital, London, U.K.
Lightman
S L
SL
Tannahill
L A
LA
D019307:1-(5-Isoquinolinesulfonyl)-2-Methylpiperazine; D000305:Adrenal Cortex Hormones / Q000502:physiology*; D000450:Aldosterone / Q000494:pharmacology; D000818:Animals; D002478:Cells, Cultured; D003346:Corticotropin-Releasing Hormone / Q000378:metabolism*; D003907:Dexamethasone / Q000494:pharmacology; D007031:Hypothalamus / Q000166:cytology / Q000196:embryology / Q000378:metabolism*; D007546:Isoquinolines / Q000494:pharmacology; D010455:Peptides / Q000494:pharmacology; D010879:Piperazines / Q000494:pharmacology; D011493:Protein Kinase C / Q000037:antagonists & inhibitors / Q000502:physiology*; D047428:Protein Kinase Inhibitors; D011494:Protein Kinases / Q000502:physiology*; D011863:Radioimmunoassay; D051381:Rats; D011919:Rats, Inbred Strains; D012701:Serotonin / Q000502:physiology*
D000305:Adrenal Cortex Hormones; D007546:Isoquinolines; D010455:Peptides; D010879:Piperazines; D047428:Protein Kinase Inhibitors; D012701:Serotonin; D000450:Aldosterone; D003907:Dexamethasone; D019307:1-(5-Isoquinolinesulfonyl)-2-Methylpiperazine; D003346:Corticotropin-Releasing Hormone; C058824:IP 20; D011494:Protein Kinases; D011493:Protein Kinase C