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Muscarinic Receptors in Human Luteinized Granulosa Cells: Activation Blocks Gap Junctions and Induces the Transcription Factor Early Growth Response Factor-1

Anatomisches Institut, Universität München (S.F., L.K., N.D., R.G., A.M.), D-80802 Munich, Germany; and Frauenklinik der Klinik am Eichert (C.H.), D-73006 Göppingen, Germany

Address all correspondence and requests for reprints to: Dr. Artur Mayerhofer, Anatomisches Institut, Universität München, Biedersteiner Strasse 29, D-80802 Munich, Germany. E-mail: . mayerhofer{at}lrz.uni- muenchen.de

Abstract

Acetylcholine (ACh) was recently described to be produced by and act on human luteinizing granulosa cells (GCs). Cholinergic agents increase intracellular calcium levels and stimulate GC proliferation via muscarinic receptors. Based on this observation and because endocrine cells of the forming human corpus luteum (CL), which are the in vivo counterparts of GCs, also proliferate in vivo, we hypothesized that ACh may be a factor involved in the regulation of the complex cellular events occurring during ovulation and formation of the CL. We addressed this possibility by investigating ACh/muscarinic receptor-mediated events in GCs. Normally, cultured GCs and their in vivo counterparts are coupled via gap junctions (GJ) consisting of connexin 43. Treatment with carbachol impaired GJ coupling of GCs within seconds, as shown in single cell, whole cell, patch-clamp studies. The cholinergic antagonist atropine and the muscarinic receptor antagonist pirenzepine specifically blocked this effect. Disruption of GJ communication of GCs is probably due to increased phosphorylation of connexin 43 at serine residues, as shown in immunoprecipitation experiments with carbachol-challenged GCs. Ovulation/formation of the CL include reprogramming of luteinizing cells, and in the rat this involves gonadotropin- induced expression of the transcription factor early growth response factor-1 (egr-1). In human GCs we found that carbachol as well as hCG can mimic this effect, as shown by cDNA arrays and semiquantitative RT-PCR. In conclusion, our results obtained in GCs suggest that endogenous, locally produced ACh may contribute to the cellular remodeling of the forming CL via muscarinic receptor/egr-1, thereby affecting proliferation, GJ communication, and regulation of gene expression in luteinizing granulosa cells.

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