HISTAMINE DIRECTLY STIMULATES GONADOTROPIN-RELEASING-HORMONE SECRETION FROM GT(1-1) CELLS VIA H1 RECEPTORS COUPLED TO PHOSPHOINOSITIDE HYDROLYSIS

It is unclear whether the central stimulating effect of histamine on G nRH secretion is exerted directly on GnRH neurosecretory neurons or in directly via multisynaptic pathways, and controversy exists about the nature of the receptors involved. The current studies were undertaken to examine whether GnRH secretion from immortalized GnRH cell lines is directly regulated by histamine and, if so, to determine the identity of the receptors and the signaling pathways coupling this action. His tamine stimulated GnRH release from GT(1-1) cells in a sustained and r eversible manner and in a dose-dependent fashion. This effect was bloc ked by the selective H-1 histamine receptor antagonist, mepyramine, bu t not by the H-2 or H-3 antagonists, ranitidine or thioperamide, respe ctively. Saturable and specific binding sites for [H-3]mepyramine were demonstrated in GT(1-1) cells, showing high affinity (apparent K-d, 3 7.8 nM) and density (apparent binding capacity, 279 fmol/mg protein) c omparable to respective values in brain tissue. Competition of [H-3]me pyramine binding was achieved with mepyramine at concentrations 3 orde rs of magnitude lower than those of ranitidine. Histamine also increas ed the production of inositol phosphates in GT(1-1) cells in a dose- a nd time-dependent manner. This response was mimicked by the selective H-1 receptor agonist 2-thiazolylethylamine and blocked by the H-1 anta gonists mepyramine, chlorpheniramine, and triprolidine. In contrast, h istamine did not alter the formation of cAMP in GT(1-1) cells. The pre sent results show a direct action of histamine on immortalized GnRH ne urons, suggesting that histamine may stimulate the reproductive axis b y activation of H-1 receptors on the surface of GnRH neurons coupled t o the formation of inositol phosphates.