The histamine H3 receptor:: gene organization, multiple isoforms, constitutive activity and molecular pharmacology

We show by genomic DNA analysis that the coding region of the rat H-3 receptor comprises three exons interrupted by two introns located in the second transmembrane domain and second intracellular loop, respectively. We have identified several isoforms of the receptor by cDNA cloning. Four variants, termed H-3(445), H-3(410), H-3(410) and H-3(397) and generated by pseudo-intron retention/deletion at the level of the third intracellular loop, display rather similar pharmacological profiles but differential tissue expression. Two short variants, termed H-3(nf1) and H-3(nf2) and corresponding to frame shift and stop codon interposition, are presumably non functional. We have assigned the human H-3 receptor gene to the telomeric region of the q arm of chromosome 20 and shown that the organization of the coding region of the human and rat H-3 receptor genes is similar. Whereas the two deduced proteins differ by only five amino acids at the level of the transmembrane domains. we show that some ligands display distinct affinities for the recombinant rat and human H-3 receptors, a difference that we assign to two aminoacids in TM3. Finally, we show that the recombinant H-3 receptor displays high constitutive activity and, having identified a neutral antagonist, we use it to demonstrate that native H-3 autoreceptors also display high constitutive activity in their control of histaminergic neuron activity in vitro and in vivo.