Selective regulation of H1 histamine receptor signaling by G protein-coupled receptor kinase 2 in uterine smooth muscle cells

Jonathon M Willets, Anthony H Taylor, Hayley Shaw, Justin C Konje, R A John Challiss

Research output: Contribution to journalArticle (Academic Journal)peer-review

46 Citations (Scopus)


Histamine stimulates uterine contraction; however, little is known regarding the mechanism or regulation of uterine histamine receptor signaling. Here we investigated the regulation of Galpha(q/11)-coupled histamine receptor signaling in human myometrial smooth muscle cells using the inositol 1,4,5-trisphosphate biosensor pleckstrin homology domain of phospholipase-delta1 tagged to enhanced green fluorescent protein and the Ca(2+)-sensitive dye Fluo-4. Histamine addition caused concentration-dependent increases in inositol 1,4,5-trisphosphate and [Ca(2+)](i) in the ULTR human uterine smooth muscle cell line and primary human myometrial cells. These effects were completely inhibited by the H(1) histamine receptor antagonist, diphenhydramine, and were unaffected by the H(2) histamine receptor antagonist, cimetidine. ULTR and primary myometrial cells were transfected with either dominant-negative G protein-coupled receptor kinases (GRKs) or small interfering RNAs targeting specific GRKs to assess the roles of this protein kinase family in H(1) histamine receptor desensitization. Dominant-negative GRK2, but not GRK5 or GRK6, prevented H(1) histamine receptor desensitization. Similarly, transfection with short interfering RNAs (that each caused >70% depletion of the targeted GRK) for GRK2, but not GRK3 or GRK6, also prevented H(1) histamine receptor desensitization. Our data suggest that histamine stimulates phospholipase C-signaling in myometrial smooth muscle cells through H(1) histamine receptors and that GRK2 recruitment is a key mechanism in the regulation of H(1) histamine receptor signaling in human uterine smooth muscle. These data provide insights into the in situ regulation of this receptor subtype and may inform pathophysiological functioning in preterm labor and other conditions involving uterine smooth muscle dysregulation.

Original languageEnglish
Pages (from-to)1893-907
Number of pages15
JournalMolecular Endocrinology
Issue number8
Publication statusPublished - Aug 2008


  • Calcium Signaling
  • Cell Line
  • Female
  • G-Protein-Coupled Receptor Kinase 2
  • G-Protein-Coupled Receptor Kinase 3
  • G-Protein-Coupled Receptor Kinases
  • Genes, Dominant
  • Histamine
  • Histamine H1 Antagonists
  • Histamine H2 Antagonists
  • Humans
  • Inositol 1,4,5-Trisphosphate
  • Mutant Proteins
  • Myocytes, Smooth Muscle
  • Myometrium
  • RNA, Small Interfering
  • Receptors, Histamine H1
  • Receptors, Histamine H2
  • Signal Transduction
  • Type C Phospholipases
  • Uterus
  • Journal Article


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