Comparison of human, mouse, rat, and guinea pig histamine H-4 receptors reveals substantial pharmacological species variation

The recently identified histamine H-4 receptor has revealed a potential new complexity for the role of histamine in the immune system. To begin to und erstand the role of this receptor in humans, one must first determine wheth er homologs exist and can be studied in lower species. To address this, we cloned the rat, mouse, and guinea pig cDNAs corresponding to the recently i dentified human histamine H-4 receptor. The rat, mouse, and guinea pig H-4 sequences are significantly different from the human H-4 sequence at 69, 68 , and 65% homology, respectively. The tissue distribution of the rat, mouse , and guinea pig H-4 receptors is similar to human in that bone marrow and spleen are the most abundant sources of expression. The human and guinea pi g H-4 receptors display the highest binding affinity for [H-3]histamine (K- D = 5 nM each), whereas the affinities for rat and mouse receptors are subs tantially lower at 136 and 42 nM, respectively. With respect to the pharmac ological profile of known H-3/H-4 ligands, even greater differences in bind ing affinities exist among the species homologs. There are also substantial differences in the signal transduction response to each of the four specie s of H-4 receptor. This work demonstrates the existence of histamine H-4 re ceptors in lower species and demonstrates that a clear knowledge of each sp ecies pharmacological profile will be essential to elucidate the role of th is receptor subtype in vivo.