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Enhanced Uterine Contractility and Stillbirth in Mice Lacking G Protein-Coupled Receptor Kinase 6 (GRK6): Implications for Oxytocin Receptor Desensitization.

Publication ,  Journal Article
Grotegut, CA; Mao, L; Pierce, SL; Swamy, GK; Heine, RP; Murtha, AP
Published in: Mol Endocrinol
April 2016

Oxytocin is a potent uterotonic agent and is used clinically for induction and augmentation of labor, as well as for prevention and treatment of postpartum hemorrhage. Oxytocin increases uterine contractility by activating the oxytocin receptor (OXTR), a member of the G protein-coupled receptor family, which is prone to molecular desensitization. After oxytocin binding, the OXTR is phosphorylated by a member of the G protein-coupled receptor kinase (GRK) family, which allows for recruitment of β-arrestin, receptor internalization, and desensitization. According to previous in vitro analyses, desensitization of calcium signaling by the OXTR is mediated by GRK6. The objective of this study was to determine the role of GRK6 in mediating uterine contractility. Here, we demonstrate that uterine GRK6 levels increase in pregnancy and using a telemetry device to measure changes in uterine contractility in live mice during labor, show that mice lacking GRK6 produce a phenotype of enhanced uterine contractility during both spontaneous and oxytocin-induced labor compared with wild-type or GRK5 knockout mice. In addition, the observed enhanced contractility was associated with high rates of term stillbirth. Lastly, using a heterologous in vitro model, we show that β-arrestin recruitment to the OXTR, which is necessary for homologous OXTR desensitization, is dependent on GRK6. Our findings suggest that GRK6-mediated OXTR desensitization in labor is necessary for normal uterine contractile patterns and optimal fetal outcome.

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Published In

Mol Endocrinol

DOI

EISSN

1944-9917

Publication Date

April 2016

Volume

30

Issue

4

Start / End Page

455 / 468

Location

United States

Related Subject Headings

  • Uterus
  • Uterine Contraction
  • Up-Regulation
  • Stillbirth
  • Receptors, Oxytocin
  • Pregnancy
  • Placenta
  • Mice, Knockout
  • Mice, Inbred C57BL
  • Male
 

Citation

APA
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Grotegut, C. A., Mao, L., Pierce, S. L., Swamy, G. K., Heine, R. P., & Murtha, A. P. (2016). Enhanced Uterine Contractility and Stillbirth in Mice Lacking G Protein-Coupled Receptor Kinase 6 (GRK6): Implications for Oxytocin Receptor Desensitization. Mol Endocrinol, 30(4), 455–468. https://doi.org/10.1210/me.2015-1147
Grotegut, Chad A., Lan Mao, Stephanie L. Pierce, Geeta K. Swamy, R Phillips Heine, and Amy P. Murtha. “Enhanced Uterine Contractility and Stillbirth in Mice Lacking G Protein-Coupled Receptor Kinase 6 (GRK6): Implications for Oxytocin Receptor Desensitization.Mol Endocrinol 30, no. 4 (April 2016): 455–68. https://doi.org/10.1210/me.2015-1147.
Grotegut, Chad A., et al. “Enhanced Uterine Contractility and Stillbirth in Mice Lacking G Protein-Coupled Receptor Kinase 6 (GRK6): Implications for Oxytocin Receptor Desensitization.Mol Endocrinol, vol. 30, no. 4, Apr. 2016, pp. 455–68. Pubmed, doi:10.1210/me.2015-1147.

Published In

Mol Endocrinol

DOI

EISSN

1944-9917

Publication Date

April 2016

Volume

30

Issue

4

Start / End Page

455 / 468

Location

United States

Related Subject Headings

  • Uterus
  • Uterine Contraction
  • Up-Regulation
  • Stillbirth
  • Receptors, Oxytocin
  • Pregnancy
  • Placenta
  • Mice, Knockout
  • Mice, Inbred C57BL
  • Male