Abstract
BackgroundThe H3 histamine receptor is a Gi-coupled GPCR that has been proven to exist in different agonist-induced states, including that defined by the protean agonist proxyfan. Several GPCRs are now known to exist in different states. For some of these, antagonist affinity measurement remain constant regardless of the state of the receptor, for others e.g. the beta-adrenoceptors, the antagonist affinity measurements vary considerably depending on which agonist-dependent state is being identified. The purpose of this study was to examine the antagonist affinity measurements at the Gi-coupling human H3 receptor, paying particular attention to measurements made in the presence of full agonists, partial agonists and the proxyfan protean agonist-induced state of the receptor.ResultsCHO cells stably expressing the human histamine H3 receptor and a CRE-SPAP reporter were used. Measurements of CRE-gene transcription and 3H-cAMP accumulation were made. A range of ligands of different agonist efficacies were determined, including some partial agonists e.g. VUF 5681. Unlike other Gi-coupled receptors, no Gs-coupled state of the receptor was detected with these ligands. Antagonist affinity measurements were constant, whether the measurements were made in the presence of a full agonist, a partial agonist or the protean agonist proxyfan.ConclusionIn contrast to all three subtypes of the beta-adrenoceptors, but in keeping with the traditional pharmacological dogma, antagonist affinity measurements remained constant at the human H3 receptor, including the medium-efficacy proxyfan-induced state of the receptor and the VUF5681-induced state of the receptor.
Highlights
The H3 histamine receptor is a Gi-coupled G-protein coupled receptor (GPCR) that has been proven to exist in different agonist-induced states, including that defined by the protean agonist proxyfan
The aim of this study was to examine the antagonist affinity measurements made at the human H3 histamine receptor stably expressed in Chinese hamster ovary (CHO) cells using a CREreporter gene system
This study examines, in detail, antagonist affinity measurements made at the different states of the H3 receptor including those induced by partial agonists, and at the medium-efficacy proxyfan induced state as distinct from the full-agonist histamine induced state of the receptor
Summary
The H3 histamine receptor is a Gi-coupled GPCR that has been proven to exist in different agonist-induced states, including that defined by the protean agonist proxyfan. The purpose of this study was to examine the antagonist affinity measurements at the Gi-coupling human H3 receptor, paying particular attention to measurements made in the presence of full agonists, partial agonists and the proxyfan protean agonist-induced state of the receptor. Antagonist affinity measurements have always played a key role in pharmacology [1,2,3] They have been vital in the initial determination of different receptor sub-types and have been a major tool in determining which receptor subtypes are present within a given tissue [9,10,11,12,13]) This led to the suggestion of the existence of a β4-adrenoceptor, many studies since, including those using knockout animals [14,15], have shown that the different antagonist affinities determined are from one receptor, the β1-adren-
Sign-in/Register to view highlights & summary Sign-in/Register to access full text options 
Talk to us
Join us for a 30 min session where you can share your feedback and ask us any queries you have
Schedule a call
