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Presence of a 5-HT₇ Receptor Positively Coupled to Adenylate Cyclase Activation in Human Granulosa-Lutein Cells¹

Institute for Hormone and Fertility Research, University of Hamburg, 22529 Hamburg, Germany

Address correspondence and requests for reprints to: Amal K. Mukhopadhyay, Institute for Hormone and Fertility Research, University of Hamburg, Grandweg 64, 22529 Hamburg, Germany. E-mail: amal{at}ihf.de

Although serotonin (5-HT) has been shown to stimulate progesterone production by human granulosa-lutein cells (hGLC), the receptor type and associated signaling pathway remain uncharacterized. We report here that 5-HT receptors in these cells are positively coupled to adenylate cyclase activity. Formation of cAMP was stimulated by 5-HT and its agonists in a dose- and time-dependent manner. Mianserin, amoxapine, and loxapine were equipotent in antagonizing 5-HT-induced cAMP formation. For both cAMP formation in cells and adenylate cyclase assay using membrane fractions, the rank order of potency for agonists of 5-HT were: 5-carboxy-aminotryptamine >5-HT> or =5-methoxytryptamine, consistent with a typical pharmacological profile of human 5-ht₇ (h5-ht₇) receptor. Sequence data of amplified complementary DNA fragments reverse transcribed from hGLC RNA revealed complete identity with published sequence of h5-ht₇ receptor complementary DNA. Northern analysis showed the presence of 2.8-kb h5-ht₇ transcripts in hGLC. The three variants h5-ht_7A, h5-ht_7B, and h5-ht_7D were also detected in hGLC. Preincubation of hGLC with 5-HT (10^-8–10^-6 M) resulted in a marked reduction in the cAMP response when the cells were subsequently stimulated with gonadotropin, and this heterologous desensitization could be reversed by 5-ht₇ receptor antagonist clozapine. These data demonstrate that h5-ht₇ receptor is present and stimulate cAMP formation in hGLC. In addition, the h5-ht₇ receptor seems to be implicated in the heterologous down-regulation hCG-stimulated cAMP response in hGLC, with a possible ramification for luteal insufficiency.

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