A study of antagonist affinities for the human histamine H2 receptor

Br J Pharmacol. 2008 Mar;153(5):1011-21. doi: 10.1038/sj.bjp.0707644. Epub 2007 Dec 24.


Background and purpose: Ligand affinity has been a fundamental concept in the field of pharmacology and has traditionally been considered to be constant for a given receptor-ligand interaction. Recent studies have demonstrated that this is not true for all three members of the G(s)-coupled beta-adrenoceptor family. This study evaluated antagonist affinity measurements at a different G(s)-coupled receptor, the histamine H(2) receptor, to determine whether antagonist affinity measurements made at a different family of GPCRs were constant.

Experimental approach: CHO cells stably expressing the human histamine H(2) receptor and a CRE-SPAP reporter were used and antagonist affinity was assessed in short-term cAMP assays and longer term CRE gene transcription assays.

Key results: Nine agonists and seven antagonists, of sufficient potency at the H(2) receptor to examine in detail, were identified. Measurements of antagonist affinity were the same regardless of the efficacy of the competing agonist, time of agonist incubation, cellular response measured or presence of a PDE inhibitor.

Conclusions and implications: Antagonist affinity at the G(s)-coupled histamine H(2) receptor obeys the accepted dogma for antagonism at GPCRs. This study further confirms that something unusual is indeed happening with the beta-adrenoceptors and is not an artefact related to the transfected cell system used. As the human histamine H(2) receptor does not behave in a similar manner to any of the human beta-adrenoceptors, it is clear that information gathered from one GPCR cannot be simply extrapolated to predict the behaviour of another GPCR. Each GPCR therefore requires careful and detailed evaluation on its own.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Binding, Competitive
  • CHO Cells
  • Cricetinae
  • Cricetulus
  • Cyclic AMP / metabolism
  • Cyclic AMP Response Element-Binding Protein / drug effects
  • Cyclic AMP Response Element-Binding Protein / metabolism
  • Forecasting
  • Genes, Reporter / drug effects
  • Histamine Agonists / pharmacology*
  • Histamine H2 Antagonists / pharmacology*
  • Humans
  • Ligands
  • Receptors, Histamine H2 / drug effects*
  • Transcription, Genetic / drug effects


  • Cyclic AMP Response Element-Binding Protein
  • Histamine Agonists
  • Histamine H2 Antagonists
  • Ligands
  • Receptors, Histamine H2
  • Cyclic AMP