Nitric oxide mediates histamine induced down-regulation of H 2 receptor mRNA and internalization of the receptor protein (R1)

Abstract

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.

Role of Macrophage-derived Histamine in Atherosclerosis<BR>&mdash; Chronic Participation in the Inflammatory Response &mdash;

“…Interestingly, the induction of these cytokines, adhesion molecules and NOS by histamine is all mediated through HH1R, which is dominantly expressed in the cells of atherosclerotic lesion (32). The predominance of HH1R in terms of endothelial gene expression may relate to the relatively rapid down-regulation of HH2R in ECs (43,44). IL-4 is known to prime endothelial cells for responses to histamine by induction of HH1R (45).…”

Alteration of intracellular histamine H2receptor cycling precedes antagonist-induced upregulation

“…Persistent treatment with an agonist induced H 2 R downregulation in CHO cells expressing rat H 2 R, and this was suggested to be mediated by posttranscriptional mRNA instability (32). In endothelial cells, persistent treatment with an agonist induced downregulation of both cell surface and mRNA expression of H 2 R (29). Because most of this evidence is based on binding assays, Western blot analysis of cell lysates, and the second messenger response, little is known about the intracellular trafficking and localization of H 2 R, especially during treatment with a H 2 R antagonist.…”

Διερεύνηση Της Διαμεσολάβησης Των Υποδοχέων Της Βραδυκινίνης Β1 Και Β2 Σε Οίδημα Προκλητό Από Ισταμίνη

“…Επιπλέον, μελέτες καταδεικνύουν ότι η μακροπρόθεσμη διέγερση ενδοθηλιακών κυττάρων με ισταμίνη έχει ως αποτέλεσμα τη μείωση της έκφρασης του mRNA του Η 2 R, μέσω της ενεργοποίησης του Η 1 R, με μεσολαβητή το μονοξείδιο του αζώτου 56 .…”