Activation of progestin receptors in female reproductive behavior: Interactions with neurotransmitters

Abstract

The steroid hormone, progesterone (P), modulates neuroendocrine functions in the central nervous system resulting in alterations in physiology and reproductive behavior in female mammals. A wide body of evidence indicates that these neural effects of P are predominantly mediated via their intracellular progestin receptors (PRs) functioning as "ligand-dependent" transcription factors in the steroid-sensitive neurons regulating genes and genomic networks. In addition to P, intracellular PRs can be activated by neurotransmitters, growth factors and cyclic nucleotides in a ligand-independent manner via crosstalk and convergence of pathways. Furthermore, recent studies indicate that rapid signaling events associated with membrane PRs and/or extra-nuclear, cytoplasmic PRs converge with classical PR activated pathways in neuroendocrine regulation of female reproductive behavior. The molecular mechanisms, by which multiple signaling pathways converge on PRs to modulate PR-dependent female reproductive behavior, are discussed in this review.

Src kinase signaling mediates estrous behavior induced by 5β-reduced progestins, GnRH, prostaglandin E2 and vaginocervical stimulation in estrogen-primed rats

“…Activation of these last neurons could release neurotransmitters capable of stimulating estrous behavior, e.g., dopamine, norepinephrine, acetylcholine, etc. (for review see, Beyer and González-Mariscal, 1986;Beyer et al, 2003;Blaustein, 2003;Etgen, 2003;Mani, 2006;Mani and Portillo, 2010) by acting on PR-Src containing neurons. Indeed, there is evidence that ring A-reduced progestins act, at least partially, through GnRH release, because the GnRH-1 receptor antagonist, antide, decreases their effects on estrous behaviors (Gómora-Arrati et al, 2008).…”

“…4, behaviorally effective agents need not directly interact with the PR-Src complex. Both GnRH and PGE 2 act on membrane receptors linked to G proteins to generate second messengers, which through kinase activation modulates various processes including estrous behaviors (for review see Mani and Portillo, 2010). Similarly, VCS releases neurotransmitters (dopamine, norepinephrine, etc., Masters et al, 1993;Quysner and Blaustein, 2001) that also act on G protein linked receptors (Etgen et al, 2001;Majewski and Musgrave, 1995;Neve et al, 2004).…”

Remodeling of the Cervix and Parturition in Mice Lacking the Progesterone Receptor B Isoform

“…Possible mechanisms, other than a fall in systemic progesterone concentrations, may mediate a local withdrawal of progesterone actions that, common to all mammals, facilitates cervical hypertrophy, extracellular collagen matrix degradation, and recruitment of immune cells, including changes in steroid metabolism in the cervix [32,39]. With little known about PGR isoforms in the uterus or cervix of rodents during pregnancy, an alternative local mechanism for progesterone to elicit normal growth, extracellular matrix remodeling, and recruitment of macrophages in the cervix before parturition may be to increase expression and activation of the PGR-A isoform [34,40,41] or regulate PGR coactivators [42] via nongenomic actions.…”

Development and Persistence of Limbic Epileptogenesis Are Impaired in Mice Lacking Progesterone Receptors

“…PRs may promote epileptogenesis by influencing synaptic plasticity and tonic inhibition in the hippocampus dentate gyrus, which is considered a gate for the excitability loop during epileptogenesis (Edwards et al, 2000;Maguire et al, 2005). PRs undergo ligand-independent activation by certain neurotransmitters (Mani and Portillo, 2010). It is likely that such signaling mechanisms may be involved in PR-mediated seizure susceptibility.…”