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Expression and Biological Effects of Endothelin-1 in Human Gonadotropin-Releasing Hormone-Secreting Neurons¹

Departments of Anatomy Histology and Forensic Medicine (G.F., G.B.V.) and Clinical Physiopathology, Endocrinology (R.M., C.P., C.C., M.S.), and Andrology Units (M.M., M.L.), University of Florence, 50134 Firenze; and Department of Experimental and Clinical Medicine (T.B.), University of Catanzaro, 88100 Catanzaro, Italy

Address correspondence and requests for reprints to: Prof. G. B. Vannelli, M.D., Department Anatomy Histology and Forensic Medicine, Viale Morgagni, 85, 50134 Firenze, Italy. E-mail: vannelli{at}unifi.it

In a previous report, we demonstrated that in FNC-B4 cells, derived and characterized from a human fetal olfactory epithelium, both sex steroids and odorants regulate GnRH secretion. We now report the presence and biological activity of endothelin (ET)-1 in this GnRH-secreting neuronal cell. By in situ hybridization and immunohistochemistry, we found gene and protein expression of ET-1 and its converting enzyme ECE-1 in both fetal olfactory mucosa and FNC-B4 cells. The presence of authentic ET-1 in the conditioned media of FNC-B4 cells was further supported by combined RIAs and high-performance liquid chromatography studies. Experiments with radiolabeled ET-1 and ET-3 strongly indicated the presence of two classes of binding sites, corresponding to the ETA (16,500 sites/cell) and the ETB receptors (8,700 sites/cell). Functional studies, using selective analogs, indicated that these two classes of receptors subserve distinct functions in human GnRH-secreting cells. The ETA receptor subtype mediated an increase in intracellular calcium and GnRH secretion. Conversely, stimulation of the ETB subtype induced DNA synthesis and mitogen-activated protein kinase p44^ERK1 expression. This is the first demonstration, in a human in vitro model, of a neuroendocrine role for ET-1 as regulator of GnRH-secreting neuron activity.

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