Ovarian acetylcholine and muscarinic receptors: Hints of a novel intrinsic ovarian regulatory system

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Abstract
More than two decades ago, the degrading enzyme of the neurotransmitter acetylcholine (ACH) was reported in nerve fibers of the rat ovary. Subsequently, it was assumed that ACH is a neurotransmitter of ovarian nerves, although the sole presence of the degrading enzyme, ACH‐esterase, does not allow such a conclusion. That ACH may be involved in the complex regulation of ovarian functions, including hormone production, was indicated by studies using, for example, granulosa cells (GCs). The lack of detailed information about both source(s) and functions of ACH in the ovary prompted us to examine sites of ovarian ACH‐synthesis and ACH‐receptor‐bearing target cells. We also started to identify functions of ACH in cultured human GCs. While ovarian innervation and recently described neuron‐like cells of the ovary were not immunoreactive for the ACH‐synthesizing enzyme, choline‐acetyl transferase (CHAT), we found immunoreactivity in GCs of rodents and primates. Isolated human and rat GCs produced ACH and contained the vesicular ACH transporter (VACHT). These results indicate that endocrine GCs are an unexpected non‐neuronal source of ACH in the ovary. Moreover, these cells and GCs in vivo contain ACH‐receptors of the muscarinic subtype (MR), namely M1R and M5R. In contrast, oocytes express M3R. MR of human GCs are functional and cholinergic stimulation is linked to rapid increases in intracellular Ca++ levels. M1/5R activation also led to increased cell proliferation of human GCs in vitro and this stimulatory effect was found to be associated with rapid disruption of gap junction communication. Ongoing studies begin to identify regulation of ion channels and altered gene expression as consequences of MR stimulation. Thus, our results outline first details of an unexpected intraovarian, non‐neuronal cholinergic system, and suggest that it may be involved in the regulation of cell proliferation in the ovary. Microsc. Res. Tech. 59:503–508, 2002.