Nitric oxide mediates histamine induced down-regulation of H2 receptor mRNA and internalization of the receptor protein (R1).
During agonist-dependent long-term stimulation of cells, histamine receptor subtypes are frequently down-regulated. However, the mechanisms underlying the modulation of receptor expression during long-term histamine stimulation have yet to be resolved. Based on our recently reported results showing an H1-mediated down-regulation of histamine H2 receptor mRNA in endothelial cells, our aim was to characterize the mechanism controlling rapid and long-term histamine-mediated modulation of H2 receptor expression in more detail. We were able to show that the histamine-induced down-regulation of H2 receptor mRNA and cell surface expression lasting for 24 h was accompanied by augmentation of the receptor protein level in the cytoplasmatic fraction of endothelial cells for this time period. Furthermore, changes in receptor protein levels in whole-cell lysate were negligible, indicating that the rapid and prolonged modulation of cell surface H2 receptor levels by histamine was regulated solely via internalization. The role of nitric oxide (NO) as a key mediator in histamine-stimulated cell responses was underlined by subsequent studies showing the attenuation of histamine-induced H2 receptor mRNA down-regulation and protein trafficking following NO synthase isozyme inhibition.
Schaefer
U
U
Biochemical and Experimental Division of the Second Department of Surgery, Ostmerheimer Strasse 200, 51109 Cologne, Germany. u.schaefer@uni-koeln.de
Schneider
A
A
Rudroff
C
C
Neugebauer
E
E
D000818:Animals; D016466:CHO Cells; D002458:Cell Fractionation; D002478:Cells, Cultured; D006224:Cricetinae; D015536:Down-Regulation; D004705:Endocytosis / Q000502:physiology; D004730:Endothelium, Vascular / Q000166:cytology / Q000378:metabolism; D006632:Histamine / Q000378:metabolism*; D006801:Humans; D007527:Isoenzymes / Q000378:metabolism; D009569:Nitric Oxide / Q000378:metabolism*; D012333:RNA, Messenger / Q000378:metabolism*; D011970:Receptors, Histamine H2 / Q000235:genetics / Q000378:metabolism*
D007527:Isoenzymes; D012333:RNA, Messenger; D011970:Receptors, Histamine H2; D009569:Nitric Oxide; D006632:Histamine