Rapid effects of estrogen to modulate G protein-coupled receptors via activation of protein kinase A and protein kinase C pathways

Martin Kelly, Andre H. Lagrange, Edward J. Wagner, Oline Ronnekleiv

Research output: Contribution to journalArticle

188 Citations (Scopus)

Abstract

17β-Estradiol (E2) rapidly (2's rapid effects. E2 acts stereospecifically with physiologically relevant concentration-dependence (EC50 = 8 nM) to cause a fourfold reduction in the potency of the μ-opioid agonist (D-Ala2-N-Me-Phe4-Gly5-ol)-enkephalin and the GABA(B) agonist baclofen to activate an inwardly rectifying K+ conductance in hypothalamic neurons. Both the nonsteroidal estrogen diethylstilbestrol and the anti-estrogen ICI 164,384 blocked E2 actions to uncouple μ-opioid receptors. Using a pharmacological Schild analysis, we found that ICI 164,384 competed for this E2 receptor with a K(e) of approximately 0.3 nM. The protein synthesis inhibitor cycloheximide did not block the estrogenic uncoupling of the μ-opioid receptor from its K+ channel, implying a rapid, nongenomic mechanism of E2 action. The effects of E2 were mimicked by the bath application of the protein kinase A (PKA) activators, forskolin and Sp-cAMP, and the protein kinase C (PKC) activator phorbol-12,13-dibutyrate. Furthermore, the selective PKA antagonists Rp-cAMP and KT5720, which have different chemical structures and modes of action, both blocked the effects of E2. In addition, the actions of E2 were blocked by the selective PKC inhibitor Calphostin C. Therefore, it appears that E2 can activate both PKA and PKC to cause a heterologous desensitization of both μ-opioid and GABA(B) receptors, which has the potential to alter synaptic transmission in many regions of the CNS.

Original languageEnglish (US)
Pages (from-to)64-75
Number of pages12
JournalSteroids
Volume64
Issue number1-2
DOIs
StatePublished - Jan 1999

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G-Protein-Coupled Receptors
Cyclic AMP-Dependent Protein Kinases
Protein Kinase C
Estrogens
Chemical activation
Opioid Receptors
Opioid Analgesics
Non-Steroidal Estrogens
GABA-B Receptor Agonists
GABA-B Receptors
Phorbol 12,13-Dibutyrate
Baclofen
Diethylstilbestrol
Protein Synthesis Inhibitors
Protein C Inhibitor
Enkephalins
Colforsin
Cycloheximide
Protein Kinase Inhibitors
Baths

Keywords

  • μ- Opioid
  • Estrogen
  • GABA(B)
  • Protein kinase A
  • Protein kinase C
  • Steroid receptor

ASJC Scopus subject areas

  • Biochemistry
  • Endocrinology
  • Molecular Biology

Cite this

Rapid effects of estrogen to modulate G protein-coupled receptors via activation of protein kinase A and protein kinase C pathways. / Kelly, Martin; Lagrange, Andre H.; Wagner, Edward J.; Ronnekleiv, Oline.

In: Steroids, Vol. 64, No. 1-2, 01.1999, p. 64-75.

Research output: Contribution to journalArticle

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