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Expression of Muscarinic Receptor Types in the Primate Ovary and Evidence for Nonneuronal Acetylcholine Synthesis¹

Anatomisches Institut, Technische Universität München (S.F., A.M.), D-80802 München, Germany; Pharmakologisches Institut, Universität Mainz (I.W.), D-55101 Mainz, Germany; Institute for Mammalian Genetics, Genome Analysis Center, GSF-National Research Center for Environment and Health (R.B.), D-85764 Neuherberg, Germany; Frauenklinik, Diakonissenkrankenhaus (W.R.), 76199 Karlsruhe-Rüppurr, Germany; Division of Neuroscience, Oregon Regional Primate Research Center-Oregon Health Sciences University (S.R.O., G.A.D.), Beaverton, Oregon 97006; and Department of Molecular Cell Biology, Weizmann Institute of Science (A.A.), Rehovot 76100, Israel

Address all correspondence and requests for reprints to: Artur Mayerhofer, M.D., Anatomisches Institut, Universitat München, Biedersteinerstrasse 29, D-80802 München, Germany. E-mail: mayerhofer{at}lrz.tu- muenchen.de.

The presence of muscarinic receptors (MR) in the ovary of different species has been recognized, but the identity of these receptors as well as ovarian sources of their natural ligand, acetylcholine (ACh), have not been determined. Because luteinized human granulosa cells (GC) in culture express functional MR, we have determined whether the group of the related MR subtypes, M1R, M3R, and M5R, are present in vivo in human and rhesus monkey ovaries. To this end, ribonucleic acids (RNAs) of different human and monkey ovaries as well as RNAs from human GC and monkey oocytes were reverse transcribed and subjected to PCR amplification, followed by sequencing of the amplified complementary DNAs. Results obtained showed that M1R, M3R, and M5R messenger RNAs are present in adult human and monkey ovaries; oocytes express exclusively the M3R subtype, whereas GC express M1R and M5R. To determine the ovarian source(s) of the natural ligand of these ACh receptors, we attempted to localize the enzyme responsible for its synthesis with the help of a monoclonal antibody recognizing choline acetyltransferase for immunohistochemistry. In neither human nor monkey sections did we detect immunoreactive choline acetyltransferase-positive fibers or nerve cells, but, surprisingly, GC of antral follicles showed prominent staining. To determine whether GC can produce ACh, human cultured GC derived from preovulatory follicles were analyzed using a high pressure liquid chromatography technique. The results showed that these cells contained ACh in concentrations ranging from 4.2–11.5 pmol/10⁶ cells. Samples of a rat granulosa cell line likewise contained ACh. Thus, the ovary contains multiple MR, and GC of antral follicles are able to synthesize ACh, the ligand of MR. We propose that ACh may serve as an as yet unrecognized factor involved in the complex regulation of ovarian function in the primate, e.g. regulation of cell proliferation or progesterone production.

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