The histamine autoreceptor is a short isoform of the H 3 receptor

Abstract

BACKGROUND AND PURPOSE: The histamine H 3 receptor was identified as the autoreceptor of brain histaminergic neurons. After its cloning, functional H 3receptor isoforms generated by a deletion in the third intracellular loop were found in the brain. Here, we determined if this autoreceptor was the long or the short isoform. EXPERIMENTAL APPROACH: We hypothesized that the deletion would affect H 3 receptor stereoselectivity. The effects of the enantiomers of two chiral ligands, Nα-methyl-α-chloromethylhistamine (NαMe-αClMeHA) and sopromidine, were investigated on cAMP formation at the H 3(445) and H 3(413) receptor isoforms, common to all species. They were further compared with their effects at autoreceptors. They were also compared on [ 35S]GTPγ[S] binding to membranes of rat cerebral cortex, striatum and hypothalamus, the richest area in autoreceptors. KEY RESULTS: The stereoselectivity of NαMe-αClMeHA enantiomers as agonists was similar at the H 3(413) receptor isoform and autoreceptors, but lower at the long isoform. While (S) sopromidine did not discriminate between the isoforms, (R) sopromidine was an antagonist at the H 3(413) receptor isoform and autoreceptors, but a full agonist at the long isoform. In rat brain, stereoselectivity of NαMe-αClMeHA was higher in the hypothalamus than in cerebral cortex or striatum, whereas the opposite pattern was found for sopromidine. CONCLUSIONS AND IMPLICATIONS: The pharmacological profiles of H 3 receptor isoforms differed markedly, showing that the function of autoreceptors was fulfilled by a short isoform, such as the H 3(413) receptor. Development of drugs selectively targeting autoreceptors might enhance their therapeutic efficacy and/or decrease incidence of side effects. © 2012 The Authors British Journal of Pharmacology © 2012 The British Pharmacological Society.