Membrane progesterone receptor expression in mammalian tissues: A review of regulation and physiological implications

Rapid Steroid Hormone Actions Initiated at the Cell Surface and the Receptors that Mediate Them with an Emphasis on Recent Progress in Fish Models

Membrane progesterone receptors (mPRs) are novel G protein-coupled receptors belonging to the progestin and adipoQ receptor family (PAQR) that mediate a variety of rapid cell surface-initiated progesterone actions in the reproductive system involving activation of intracellular signaling pathways (ie nonclassical actions) The mPRs are highly expressed in the brain, but research on their neural functions has only been conducted in a single neuronal cell line, GT1-7 cells, which have negligible nuclear progesterone receptor (PR) expression GT1-7 cells express mPRα and mPRβ on their plasma membranes which is associated with the presence of high-affinity, specific [(3)H]-progesterone receptor binding The neurosteroid, allopregnanolone, is an effective ligand for recombinant mPRα with a relative binding affinity of 76% that of progesterone Allopregnanolone acts as a potent mPR agonist on GT1-7 cells, mimicking the progesterone-induced decrease in cAMP accumulation and its antiapoptotic actions at low nanomolar concentrations The decrease in cAMP levels is associated with rapid progesterone-induced downregulation of GnRH pulsatile secretion from perifused GT1-7 cells The recent suggestion that mPRs are alkaline ceramidases and mediate sphingolipid signaling is not supported by empirical evidence that TNFα does not bind to mPRs overexpressed in human cells and that exogenous sphingomyelinase is ineffective in mimicking progestin actions through mPRs to induce meiotic maturation of fish oocytes Taken together, these recent studies indicate that mPRs mediate neuroprotective effects of progesterone and allopregnanolone and are also the likely intermediaries in progesterone-induced inhibition of pulsatile GnRH secretion in GT1-7 cells

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Membrane progesterone receptors: evidence for neuroprotective, neurosteroid signaling and neuroendocrine functions in neuronal cells.

Progesterone and Neuroprotection

Distribution of membrane progesterone receptor alpha in the male mouse and rat brain and its regulation after traumatic brain injury

In addition to the activation of classical progestin receptor-dependent genomic pathway, progesterone (P) can activate nonclassical, membrane-initiated signaling pathways in the brain. We recently demonstrated rapid P activation of second-messenger kinases, protein kinase A, and protein kinase C in the ventromedial nucleus (VMN) and preoptic area (POA) of rat brain. To determine whether P can activate yet another Ca+2 dependent kinase, we examined the rapid P modulation of calcium and calmodulin-dependent protein kinase II (CaMKII) in the VMN and POA in female rats. A rapid P-initiated activation of CaMKII basal activity was observed in the VMN but not the POA at 30 min. Estradiol benzoate (EB) priming enhanced this CaMKII basal activity in both the VMN and POA. CaMKII protein levels and phosphorylation of Thr-286 moiety on CaMKII, however, remained unchanged with EB and/or P treatments, suggesting that the changes in the CaMKII kinase activity are due to rapid P modulation of the kinase activity and not its synthesis or autoactivation. Furthermore, intracerebroventricular (icv) administration of a CaMKII-specific inhibitor, KN-93, 30 min prior to the P infusion, in EB-primed, ovariectomized female rats inhibited CaMKII activation but not protein kinase A and protein kinase C activities. Interestingly, icv administration of KN-93 30 min prior to P infusion (icv) resulted in a reduction but not total inhibition of P-facilitated lordosis response in EB-primed female rats. These observations suggest a redundancy or, alternately, a hierarchy in the P-regulated activation of kinase signaling cascades in female reproductive behavior.

Nonclassical mechanisms of progesterone action in the brain: II. Role of calmodulin-dependent protein kinase II in progesterone-mediated signaling in the hypothalamus of female rats.

The modulation of gene regulation by progesterone (P) and its classical intracellular regulation by progestin receptors in the brain, resulting in alterations in physiology and behavior has been well studied. The mechanisms mediating the short latency effects of P are less well understood. Recent studies have revealed rapid nonclassical signaling action of P involving the activation of intracellular signaling pathways. We explored the involvement of protein kinase C (PKC) in P-induced rapid signaling in the ventromedial nucleus of the hypothalamus (VMN) and preoptic area (POA) of the rat brain. Both the Ca2+-independent (basal) PKC activity representing the activation of PKC by the in vivo treatments and the Ca+2-dependent (total) PKC activity assayed in the presence of exogenous cofactors in vitro were determined. A comparison of the two activities demonstrated the strength and temporal status of PKC regulation by steroid hormones in vivo. P treatment resulted in a rapid increase in basal PKC activity in the VMN but not the POA. Estradiol benzoate priming augmented P-initiated increase in PKC basal activity in both the VMN and POA. These increases were inhibited by intracerebroventricular administration of a PKC inhibitor administered 30 min prior to P. The total PKC activity remained unchanged demonstrating maximal PKC activation within 30 min in the VMN. In contrast, P regulation in the POA significantly attenuated total PKC activity +/- estradiol benzoate priming. These rapid changes in P-initiated PKC activity were not due to changes in PKC protein levels or phosphorylation status.

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Nonclassical mechanisms of progesterone action in the brain: I. Protein kinase C activation in the hypothalamus of female rats.

Context—Catecholamines and inflammatory mediators, with elevated levels after brain death, are associated with reduced function and survival of transplanted organs. Enteral nutrition reduces tissue damage and may benefit organs.Objective—To evaluate the effects of immunomodulating enteral nutrition in organ donors.Design—Prospective, randomized, open-label study.Setting—Intensive care unit.Patients—Thirty-six brain-dead organ donors.Interventions—Donors were randomized to receive enteral nutrition containing omega-3 polyunsaturated fatty acid, antioxidants, and glutamine or standard care (fasting). Donors received hormonal replacement therapy of corticosteroid, levothyroxine, dextrose, and insulin.Main Outcome Measures—Gastrointestinal assimilation (measured by 13carbon-labeled uracil breath analysis), quantity of organs recovered, resting energy expenditure, urine level of urea nitrogen, and serum levels of albumin, prealbumin, interleukin 6, tumor necrosis factor-α, and C-reactive protein were evaluated...

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Anthony N. Moore

Papers

Nonclassical mechanisms of progesterone action in the brain: II. Role of calmodulin-dependent protein kinase II in progesterone-mediated signaling in the hypothalamus of female rats.

Nonclassical mechanisms of progesterone action in the brain: I. Protein kinase C activation in the hypothalamus of female rats.

Randomized Trial to Evaluate Nutritional Status and Absorption of Enteral Feeding after Brain Death