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Estrogen regulation of the dopamine-activated GIRK channel in pituitary lactotrophs: implications for regulation of prolactin release during the estrous cycle.

ABSTRACT: Prolactin (PRL), synthesized and secreted from lactotrophs of the anterior pituitary gland, is tonically inhibited by hypothalamic dopamine (DA) throughout the female reproductive (estrous) cycle. Our laboratory has shown that DA hyperpolarizes these cells by activating G protein-coupled inwardly rectifying K(+) (GIRK) channels; however, this response is only observed on proestrus. While the cellular mechanisms that allow for functional expression of this unique DA-signaling pathway are unclear, we hypothesized that activation of the DA-GIRK effector pathway is due to the rise in circulating estrogen (E?) during the preceding day of diestrus. Thus, we examined the effects of E? on primary lactotrophs isolated from female rats. Treatment with a physiological concentration of E? (40-80 pg/ml, in vivo or in vitro) induced a proestrous phenotype in diestrous lactotrophs. These cells exhibited a DA-induced membrane hyperpolarization, as well as a secretory rebound of PRL following DA withdrawal (characteristic of proestrous cells). Internal dialysis of GTP?S demonstrated that E? exposure enabled functional expression of GIRK channels, and this regulation by E? did not involve the D?R. The effect of E? was blocked by the receptor antagonist, ICI 182,780, and by the protein synthesis inhibitor, cycloheximide. Single-cell analysis revealed increased mRNA expression of GIRK channel subunits in E?-treated lactotrophs. While E? is known to have multiple actions on the lactotroph, the present findings illuminate a novel action of E? in lactotrophs-regulation of the expression of a DA effector, the GIRK channel.

SUBMITTER: Christensen HR

PROVIDER: S-EPMC3290005 | biostudies-literature | 2011 Sep

REPOSITORIES: biostudies-literature

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Estrogen regulation of the dopamine-activated GIRK channel in pituitary lactotrophs: implications for regulation of prolactin release during the estrous cycle.

Christensen Heather R HR Zeng Qinghua Q Murawsky Michael K MK Gregerson Karen A KA

American journal of physiology. Regulatory, integrative and comparative physiology 20110608 3

Prolactin (PRL), synthesized and secreted from lactotrophs of the anterior pituitary gland, is tonically inhibited by hypothalamic dopamine (DA) throughout the female reproductive (estrous) cycle. Our laboratory has shown that DA hyperpolarizes these cells by activating G protein-coupled inwardly rectifying K(+) (GIRK) channels; however, this response is only observed on proestrus. While the cellular mechanisms that allow for functional expression of this unique DA-signaling pathway are unclear, ...[more]

PMID: 21653876

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Project description:Mesolimbic dopamine transmission is dysregulated in multiple psychiatric disorders, including addiction. Previous studies found that the endogenous GABAergic steroid (3α,5α)-3-hydroxy-5-pregnan-20-one (allopregnanolone) modulates dopamine levels in the nucleus accumbens and prefrontal cortex. As allopregnanolone is a potent positive allosteric modulator of GABAA receptors, and GABAA receptors can regulate dopamine release, we hypothesized that allopregnanolone would reduce phasic fluctuations in mesolimbic dopamine release that are important in learning and reward processing. We used fast-scan cyclic voltammetry in anesthetized female and male rats to measure dopamine release in the nucleus accumbens evoked by electrical stimulation of the ventral tegmental area, before and after administration of allopregnanolone. Allopregnanolone (7.5-25 mg/kg, IP) reduced evoked dopamine release in both male and female rats, compared to β-cyclodextrin vehicle. In males, all doses of allopregnanolone decreased dopamine transmission, with stronger effects at 15 and 25 mg/kg allopregnanolone. In females, 15 and 25 mg/kg allopregnanolone reduced dopamine release, while 7.5 mg/kg allopregnanolone was no different from vehicle. Since allopregnanolone is derived from progesterone, we hypothesized that high endogenous progesterone levels would result in lower sensitivity to allopregnanolone. Consistent with this, females in proestrus (high progesterone levels) were less responsive to allopregnanolone than females in other estrous cycle stages. Furthermore, 30 mg/kg progesterone reduced evoked dopamine release in males, similar to allopregnanolone. Our findings confirm that allopregnanolone reduces evoked dopamine release in both male and female rats. Moreover, sex and the estrous cycle modulated this effect of allopregnanolone. These results extend our knowledge about the pharmacological effects of neurosteroids on dopamine transmission, which may contribute to their therapeutic effects.

Dataset Information

Estrogen regulation of the dopamine-activated GIRK channel in pituitary lactotrophs: implications for regulation of prolactin release during the estrous cycle.

Publications

Estrogen regulation of the dopamine-activated GIRK channel in pituitary lactotrophs: implications for regulation of prolactin release during the estrous cycle.

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