Am J Physiol Cell Physiol Journal of Neurophysiology
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Am J Physiol Cell Physiol 277: C563-C571, 1999;
0363-6143/99 $5.00
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Vol. 277, Issue 3, C563-C571, September 1999

CFTR is functionally active in GnRH-expressing GT1-7 hypothalamic neurons

Richard T. Weyler1, Karin A. Yurko-Mauro2, Ronald Rubenstein3, Wouter J. W. Kollen3, William Reenstra2,4, Steven M. Altschuler1, Marie Egan5, and Andrew E. Mulberg1

Divisions of 1 Gastroenterology and Nutrition and 3 Pulmonary Medicine, Department of Pediatrics, Children's Hospital of Philadelphia, Philadelphia, Pennsylvania 19104; Departments of 2 Clinical Research and 4 Pediatrics, A. I. duPont Hospital for Children, Thomas Jefferson University, Wilmington, Delaware 19803; and 5 Division of Pulmonary Medicine, Yale University School of Medicine, New Haven, Connecticut 06520

We have demonstrated the expression of the cystic fibrosis transmembrane conductance regulator (CFTR) gene, mRNA, and protein within the rat and human brains, in areas regulating sexual differentiation and function. We have found that GT1-7, a gonadotropin-releasing hormone (GnRH)-secreting hypothalamic neuronal cell line, expresses the CFTR gene, mRNA, and protein and cAMP-dependent 36Cl efflux. A linear 7-pS Cl- conductance, which is stimulated by ATP and cAMP analogs and inhibited by glibenclamide, consistent with CFTR activity, has been identified in GT1-7 cells. Antisense oligo(dN) generated against exon 10 of the CFTR gene transcript (mRNA) inhibit GnRH secretion into media [312 ± 73, 850 ± 150, 963 ± 304, and 912 ± 74 pg GnRH/4 × 106 cells for antisense, sense, missense, and no oligo(dN), respectively; P < 0.029 for antisense oligo(dN)-treated vs. normal cells]. No changes in intracellular synthesis of GnRH were noted [1,400 ± 371 and 1,395 ± 384 pg GnRH/4 × 106 cells for antisense and sense oligo(dN), respectively]. Antisense oligo(dN), but not sense or missense oligo(dN), inhibited cAMP-dependent 36Cl efflux. The expression of CFTR protein, detected by Western blotting, was also inhibited 68% by preincubation of cells with antisense oligo(dN). GT1-7 hypothalamic neurons express the CFTR gene, mRNA, and protein, which modulate neurosecretion. Abnormal neuropeptide vesicle trafficking by mutant CFTR may help to explain some of the diverse manifestations of cystic fibrosis.

neuropeptide secretion; vesicle trafficking; infertility; congenital bilateral absence of the vas deferens; cystic fibrosis transmembrane conductance regulator; gonadotropin-releasing hormone


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