Rapid desensitization and slow recovery of the cyclic AMP response mediated by histamine H(2) receptors in the U937 cell line

Biochem Pharmacol. 2000 Jul 15;60(2):159-66. doi: 10.1016/s0006-2952(00)00295-1.


The present study focused on the desensitization process of the H(2) receptor in U937 cells and the recovery of the cyclic AMP (cAMP) response. Treatment of U937 leukemic cells with the H(2) histamine receptor agonists (+/-)-N(1)-[3-(3, 4-difluorophenyl)-3-(pyridin-2-yl)propyl]-N(2)-[3-(1H-imidazol-4-yl)p ropyl]guanidine (BU-E-75) and amthamine produced a rapid desensitization characterized by decreased cAMP production (T(1/2) = 20 min). Pretreatment with 10 microM BU-E-75 did not induce modifications in the responses to prostaglandin E(2), isoproterenol, or forskolin. H(2) receptor desensitization was not affected by protein kinase A and C inhibitors, but was reduced drastically by Zn(2+) and heparin, known to act as inhibitors of G protein-coupled receptor kinases. Recovery studies of the cAMP response showed that cAMP levels reached 50% of the initial values within 5 hr. Furthermore, desensitization produced an important decrease in the basal level of this cyclic nucleotide. The minimal value was observed 12 hr later, and corresponded to approximately 1.3% of the initial basal level (7.5 vs 0.1 pmol/10(6) cells). This result could be explained by an increase in phosphodiesterase activity following 10 microM BU-E-75 treatment. When cells were exposed for 2 hr to an H(2) agonist, binding assays showed no modification in the number of H(2) receptors; internalization began just after 8 hr. Although the initial desensitization seems to involve G protein-coupled receptor kinases, results indicate that additional mechanisms of regulation were triggered by the H(2) agonists.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Cimetidine / analogs & derivatives
  • Cimetidine / pharmacology
  • Cyclic AMP / metabolism*
  • Cyclic AMP-Dependent Protein Kinases / metabolism
  • Guanidines / pharmacology
  • Histamine Agonists / pharmacology
  • Histamine H2 Antagonists / pharmacology
  • Humans
  • Imidazoles / pharmacology
  • Phosphoric Diester Hydrolases / metabolism
  • Radioligand Assay
  • Receptors, Histamine H2 / drug effects
  • Receptors, Histamine H2 / metabolism*
  • Tritium
  • U937 Cells
  • beta-Adrenergic Receptor Kinases


  • Guanidines
  • Histamine Agonists
  • Histamine H2 Antagonists
  • Imidazoles
  • Receptors, Histamine H2
  • Tritium
  • BU-E 75
  • Cimetidine
  • Cyclic AMP
  • Cyclic AMP-Dependent Protein Kinases
  • beta-Adrenergic Receptor Kinases
  • Phosphoric Diester Hydrolases
  • tiotidine