The histamine autoreceptor is a short isoform of the H3 receptor

BACKGROUND AND PURPOSE The histamine H3 receptor was identified as the autoreceptor of brain histaminergic neurons. After its cloning, functional H3 receptor 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 H3 receptor stereoselectivity. The effects of the enantiomers of two chiral ligands, Na-methyl-a-chloromethylhistamine (NaMe-aClMeHA) and sopromidine, were investigated on cAMP formation at the H3(445) and H3(413) receptor isoforms, common to all species. They were further compared with their effects at autoreceptors. They were also compared on [35S]GTP?[S] binding to membranes of rat cerebral cortex, striatum and hypothalamus, the richest area in autoreceptors. KEY RESULTS The stereoselectivity of NaMe-aClMeHA enantiomers as agonists was similar at the H3(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 H3(413) receptor isoform and autoreceptors, but a full agonist at the long isoform. In rat brain, stereoselectivity of NaMe-aClMeHA 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 H3 receptor isoforms differed markedly, showing that the function of autoreceptors was fulfilled by a short isoform, such as the H3(413) receptor. Development of drugs selectively targeting autoreceptors might enhance their therapeutic efficacy and/or decrease incidence of side effects.