Multiple signaling pathways of histamine H2 receptors. Identification of an H2 receptor-dependent Ca2+ mobilization pathway in human HL-60 promyelocytic leukemia cells

J Biol Chem. 1989 Nov 5;264(31):18356-62.

Abstract

In order to analyze the complex activities of histamine H2 receptor activation on neutrophils, human HL-60 promyelocytic leukemia cells were differentiated into neutrophils by incubation with dimethyl sufoxide, loaded with the Ca2+-sensitive indicator dyes, indo-1 or fura-2, and the levels of intracellular Ca2+ ([Ca2+]i) measured in a fluorescent-activated cell sorter and fluorimeter, respectively. Histamine increased [Ca2+]i in a dose-dependent manner with a half-maximal concentration (EC50) of approximately 10(-6) to 10(-5) M, which exhibited H2 receptor specificity. Prostaglandin E2 and isoproterenol also induced [Ca2+]i mobilization in HL-60 cells, whereas the cell permeable form of cAMP and forskolin failed to increase [Ca2+]i. Since H2-receptor mediated [Ca2+]i mobilization was not inhibited by reducing the concentration of extracellular Ca2+ nor by the addition of Ca2+ channel antagonists, LaCl3 and nifedipine, [Ca2+]i mobilization is due to the release of Ca2+ from intracellular stores. Furthermore, both 10(-4) M histamine and 10(-6) M fMet-Leu-Phe increased the levels of 1,4,5-inositol trisphosphate. However, histamine-induced mobilization of [Ca2+]i was inhibited by cholera toxin but not by pertussis toxin, whereas the action of fMet-Leu-Phe was inhibited by pertussis toxin but not by cholera toxin. These data suggest that H2 receptors on HL-60 cells are coupled to two different cholera toxin-sensitive G-proteins and activate adenylate cyclase and phospholipase C simultaneously.

Publication types

  • Research Support, Non-U.S. Gov't
  • Research Support, U.S. Gov't, P.H.S.

MeSH terms

  • Calcium / metabolism*
  • Calcium Channel Blockers / pharmacology
  • Cell Differentiation / drug effects
  • Cholera Toxin / pharmacology
  • Colforsin / pharmacology
  • Cyclic AMP / pharmacology
  • Dimethyl Sulfoxide / pharmacology
  • Dinoprostone / pharmacology
  • Histamine / pharmacology
  • Humans
  • Inositol 1,4,5-Trisphosphate / metabolism
  • Isoproterenol / pharmacology
  • Kinetics
  • Leukemia, Promyelocytic, Acute / metabolism*
  • N-Formylmethionine Leucyl-Phenylalanine / pharmacology
  • Neutrophils / drug effects
  • Neutrophils / metabolism*
  • Receptors, Histamine H2 / physiology*
  • Signal Transduction / physiology*
  • Tumor Cells, Cultured

Substances

  • Calcium Channel Blockers
  • Receptors, Histamine H2
  • Colforsin
  • N-Formylmethionine Leucyl-Phenylalanine
  • Histamine
  • Inositol 1,4,5-Trisphosphate
  • Cholera Toxin
  • Cyclic AMP
  • Dinoprostone
  • Isoproterenol
  • Calcium
  • Dimethyl Sulfoxide