Functions of Membrane Progesterone Receptors (mPRs, PAQRs) in Nonreproductive Tissues

Gender differences in a wide variety of physiological parameters have implicated the ovarian hormones, estrogens and progesterone, in the regulation of numerous nonreproductive tissue functions. Rapid, nongenomic (nonclassical) progesterone actions mediated by membrane progesterone receptors (mPRs), which belong to the progestin and adipoQ receptor family, have been extensively investigated in reproductive and nonreproductive tissues since their discovery in fish ovaries 20 years ago. The 5 mPR subtypes (alpha, beta, gamma, delta, epsilon) are widely distributed in vertebrate tissues and are often expressed in the same cells as the nuclear progesterone receptor (PR) and progesterone receptor membrane component 1, thereby complicating investigations of mPR-specific functions. Nevertheless, mPR-mediated progesterone actions have been identified in a wide range of reproductive and nonreproductive tissues and distinguished from nuclear PR-mediated ones by knockdown of these receptors with siRNA in combination with a pharmacological approach using mPR- and PR-specific agonists. There are several recent reviews on the roles of the mPRs in vertebrate reproduction and cancer, but there have been no comprehensive assessments of mPR functions in nonreproductive tissues. Therefore, this article briefly reviews mPR functions in a broad range of nonreproductive tissues. The evidence that mPRs mediate progesterone and progestogen effects on neuroprotection, lordosis behavior, respiratory control of apnea, olfactory responses to pheromones, peripheral nerve regeneration, regulation of prolactin secretion in prolactinoma, immune functions, and protective functions in vascular endothelial and smooth muscle cells is critically reviewed. The ubiquitous expression of mPRs in vertebrate tissues suggests mPRs regulate many additional nonreproductive functions that remain to be identified.