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

Abstract

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.

Rapid 1α,25(OH)2D3 membrane-mediated activation of Ca2+/calmodulin-dependent protein kinase II in growth plate chondrocytes requires Pdia3, PLAA and caveolae

“…Previous studies have shown that steroid hormones stimulate a rapid increase in CaMKII activity (9). The present study shows that the membrane actions of 1a,25(OH) 2 D 3 activate CaMKII.…”

Membrane progestin receptors in the midbrain ventral tegmental area are required for progesterone-facilitated lordosis of rats

“…Additionally, there is some evidence that P 4 may also have actions independent of nPRs, involving non-classical targets, such as neurotransmitters (e.g. GABA, glutamate), and signal transduction pathways, in the VMH for lordosis (Balasubramanian et al, 2008a,b; Frye, 2001c; Georgescu and Pfaus, 2006a,b; González-Flores et al, 2010; Hoffman et al, 2002). A question not addressed in the present study was the role of mPRs in the VMH as a membrane target for progestins' actions for lordosis.…”

Progesterone and neuroprotection

“…For example, the effect of progesterone has been reported in the brain of PR knock-out (PRKO) mice (Krebs et al, 2000), suggesting PRs other than the classical PR may mediate the effect of progesterone in the CNS. In fact, several lines of evidence recently obtained suggest that the rapid effects of progesterone are mediated by cell membrane-associated PRs expressed in the brain (Balasubramanian et al, 2008a, b; Liu et al, 2009; Tokmakov and Fukami, 2009). If nothing else, progesterone’s high degree of lipophilicity (having a logP value, or octanol/water partition coefficient, of approximately 4), may be consistent with the idea that progesterone interacts with a plasma membrane associated receptor.…”