Abstract

We identified the cDNAs of three functional rat H₃ receptor isoforms (H_3A, H_3B, and H_3C) and one nonfunctional truncated H₃ receptor (H_3T). The H_3A, H_3B, and H_3C receptor isoforms vary in the length of their third intracellular loop; the H_3B and H_3C receptor lack 32 and 48 amino acids, respectively. Transient expression of the H_3A, H_3B, and H_3C receptors in COS-7 cells results in high affinity binding for the H₃ antagonist [¹²⁵I]iodophenpropit, which is displaced by selective H₃ agonists and antagonists. The three isoforms differentially couple to the G_i protein-dependent inhibition of adenylate cyclase or stimulation of p44/p42 mitogen activated protein kinase (MAPK), a new signaling pathway for the H₃ receptor. Whereas the H_3A receptor was less effective in inhibiting forskolin-induced cAMP production compared with the H_3B or H_3C receptor, this isoform was more effective in the stimulation of p44/p42 MAPK. The H₃receptor isoforms also displayed differential CNS expression in key areas involved in regulation of sensory, endocrine, and cognitive functions. A differential H₃ receptor isoform expression was seen in, for example, hippocampus, where a characteristic dorsoventral distribution was revealed. Differential H₃receptor expression was also characteristic for the cerebellum, indicating possible histaminergic regulation of motor functions. The identification of these new H₃ receptor isoforms and their specific signaling properties adds a new level of complexity to our understanding of the role of histamine, and the H₃ receptor in brain function. The heterogeneous distribution of the isoforms suggests that H₃ receptor isoform-specific regulation is important in several brain functions.