Multiple signaling pathways of histamine H2 receptors.
Histamine H2 receptor (H2R) has been shown to be coupled to adenylate cyclase. However, we have previously demonstrated that H2R-specific stimulation also activated phospholipase C in human HL-60 promyelocytic leukemia cells (Mitsuhashi M. et al. J. Biol. Chem. 264:18356, 1989). We have extended these studies on HL-60 cells to investigate whether histamine-bovine serum albumin conjugates (HA-BSA) specifically recognize H2R and activate phospholipase C pathways. Both histamine (HA) and HA-BSA increased intracellular concentrations of calcium in a H2R specific manner. However, HA-induced calcium mobilization was transient and returned to the basal level within 1-2 min, whereas HA-BSA-induced calcium mobilization was sustained for more than 10 min as a result of the additional influx of extracellular calcium. More interestingly, fluorescein (FITC) labeled HA-BSA was less incorporated into cytosols and present in the membrane fractions for more than 60 min, whereas membrane-bound FITC-HA was rapidly incorporated into cytosols. Furthermore, the levels of inositol 1,3,4,5-tetrakisphosphate, which is known to activate calcium channels were more sustained after HA-BSA stimulation than those of HA alone. These data suggest that H2R activation mechanism is more complex and may be modified by this slowly metabolized "compound ligand".
Mitsuhashi
M
M
Department of Medicine, University of California Medical Center, San Francisco 94143.
Payan
D G
DG
D002118:Calcium / Q000378:metabolism; D004789:Enzyme Activation / Q000187:drug effects; D016650:Fluorescein-5-isothiocyanate; D005452:Fluoresceins; D005456:Fluorescent Dyes; D006632:Histamine / Q000378:metabolism / Q000494:pharmacology; D006801:Humans; D007295:Inositol Phosphates / Q000378:metabolism; D015473:Leukemia, Promyelocytic, Acute; D011970:Receptors, Histamine H2 / Q000502:physiology*; D012710:Serum Albumin, Bovine / Q000378:metabolism / Q000494:pharmacology; D015398:Signal Transduction; D013861:Thiocyanates; D014407:Tumor Cells, Cultured; D010738:Type C Phospholipases / Q000378:metabolism
D005452:Fluoresceins; D005456:Fluorescent Dyes; D007295:Inositol Phosphates; D011970:Receptors, Histamine H2; D013861:Thiocyanates; C069369:histamine-bovine serum albumin conjugate; D012710:Serum Albumin, Bovine; D006632:Histamine; D010738:Type C Phospholipases; D016650:Fluorescein-5-isothiocyanate; D002118:Calcium