Activation of the Alpha 7 Nicotinic Acetylcholine Receptor (CHRNA7) Limits Hypoxia-induced Inflammatory Responses and Regulates Collagens in Cultured Human Granulosa Cells

The alpha 7 nicotinic acetylcholine (ACh) receptor (CHRNA7) is targeted by ACh, choline and exogenous chemicals, including nicotine and insecticides. According to database searches, it is expressed by several cell types of the human ovary, including granulosa cells (GCs). This expression site was confirmed by immunohistochemistry in human and nonhuman primate ovaries. Cultured human GCs, derived from in vitro-fertilization, express functional CHRNA7, indicated by acutely elevated intracellular Ca2+ levels upon addition of the selective CHRNA7 agonist PNU 282987. Heterogeneity in this acute response may be due, in part, to the varying expression of the human-specific channel variant CHRFAM7A, which acts as a negative regulator. CHRNA7 activation is reported to dampen inflammatory reactions in non-neuronal cells, and in cultured human GCs, as recently reported, inflammatory responses are induced by 1% O2. Studies in GCs exposed to 1% O2 may mirror the physiological situation in the periovulatory human follicle, and we found that PNU 282987 significantly decreased the low O2-induced elevations of IL6, CXCL8 and IL1B. Proteomic studies identified further consequences in human GCs exposed to 1% O2. Thus, PNU 282987 increased abundances of 31 proteins and decreased abundances of 6 proteins. Of note, several collagens were among the decreased proteins, which might be novel ovarian biomarkers for GC luteinization and oocyte quality. Our results imply roles of endogenous CHRNA7 activators and possibly exogenous chemicals in limiting inflammatory responses and in the regulation of other human GC functions. This influence may depend on the relative abundance of CHRNA7 and translation of CHRFAM7A.