Identification of rat H-3 receptor isoforms with different brain expression and signaling properties

We identified the cDNAs of three functional rat H-3 receptor isoforms (H-3A , H-3B, and H-3C) and one nonfunctional truncated H-3 receptor (H-3T). The H-3A, H-3B, and H-3C receptor isoforms vary in the length of their third in tracellular loop; the H3B and H3C receptor lack 32 and 48 amino acids, resp ectively. Transient expression of the H-3A, H-3B, and H-3C receptors in COS -7 cells results in high affinity binding for the H-3 antagonist [I-125] io dophenpropit, which is displaced by selective H-3 agonists and antagonists. The three isoforms differentially couple to the G(i) protein-dependent inh ibition of adenylate cyclase or stimulation of p44/p42 mitogen activated pr otein kinase (MAPK), a new signaling pathway for the H-3 receptor. Whereas the H-3A receptor was less effective in inhibiting forskolin-induced cAMP p roduction compared with the H-3B or H-3C receptor, this isoform was more ef fective in the stimulation of p44/p42 MAPK. The H-3 receptor isoforms also displayed differential CNS expression in key areas involved in regulation o f sensory, endocrine, and cognitive functions. A differential H-3 receptor isoform expression was seen in, for example, hippocampus, where a character istic dorsoventral distribution was revealed. Differential H-3 receptor exp ression was also characteristic for the cerebellum, indicating possible his taminergic regulation of motor functions. The identification of these new H -3 receptor isoforms and their specific signaling properties adds a new lev el of complexity to our understanding of the role of histamine, and the H-3 receptor in brain function. The heterogeneous distribution of the isoforms suggests that H-3 receptor isoform-specific regulation is important in sev eral brain functions.