Genomics meets histamine receptors: new subtypes, new receptors.

Whether the job is waking the brain after a peaceful sleep, initiating gastric secretion when dinner is served or orchestrating the elements of inflammation after a mosquito bite, histamine has been a known biological messenger for decades (Green, 1964; Eichler and Farah, 1966). At the end of the twentieth century, in the midst of the genomics and bioinformatics revolution, researchers in this field knew of the existence of only three histamine receptors (H1, H2, and H3). But histamine receptors are catching up! Not only have multiple forms of the H3 receptor recently been described but also a new histamine receptor, H4, has now been identified. The presently-known histamine receptors (H1, H2, and H3) are all G protein-coupled molecules and they transduce extracellular signals via Gq, Gs, and Gi/o, respectively (Hill et al., 1997; Lovenberg et al., 1999). Not surprisingly, classic pharmacology studies (Ash and Schild, 1966; Black et al., 1972; Arrang et al., 1983) argued for their existence decades before they were cloned (Gantz et al., 1991; Yamashita et al., 1991; Lovenberg et al., 1999). Likewise, heterogeneity among H3 receptors had long been suspected based on agonist kinetics (West et al., 1990), radioligand binding characteristics (Cumming et al., 1991; Alves-Rodrigues et al., 1996), peripheral versus central nervous system pharmacology (Leurs et al., 1996; Harper et al., 1999), and other functional studies (Schlicker et al., 1992; Schworer et al., 1994), but the absence of subtype-selective compounds prevented firm classification. Although the H1 and H2 receptors were cloned nearly a decade ago (Gantz et al., 1991; Yamashita et al., 1991), the H3 receptor was not cloned until 1999 (Lovenberg et al., 1999). However, this elucidation of the H3 receptor structure in man and other species (Lovenberg et al., 1999, 2000; Tardivel-Lacombe et al., 2000; Drutel et al., 2001) quickly led to discoveries of the H3 receptor subtypes and the closely related H4 receptor, which are discussed presently. Recent molecular studies have shown that a single form of the H3 gene can give rise to multiple mRNA isoforms, named H3A, H3B, and H3C in the rat (Drutel et al., 2001), and H3L and H3S in the guinea pig (Tardivel-Lacombe et al., 2000). The variants all are known to differ in the structure of their third cytoplasmic loops, although the relevant splicing mechanisms remain uncertain (Tardivel-Lacombe et al., 2000; Drutel et al., 2001). Thus far, similar variants in human samples have not been identified (Liu et al., 2000), although the existence of multiple, somewhat different H3 isoforms in humans was reported recently (Wellendorf et al., 2000). The H3 receptor isoform that seems to be most predominant in human brain corresponds to the rat H3A and the guinea pig H3L. In the January 2001 issue of this journal, pharmacological differences in the H3 receptor subtypes, as well as evidence for a differential distribution of the subtypes in rat brain, were presented (Drutel et al., 2001). Considering the current interest in the H3 autoreceptor (Morisset et al., 2000), the ability of the H3 heteroreceptor to regulate the activity of many brain transmitters (Hill et al., 1997; Hough, 1999) and the potential for developing new H3 pharmacotherapies [e.g., in attention deficit/hyperactivity disorder, Alzheimer’s disease, obesity, and others (Leurs et al., 1998; Tedford, 1998)], the characterization of the H3 receptor subtypes is of considerable significance. Phylogenetic (Leurs et al., 2000) and homology analysis (Lovenberg et al., 1999) of the H3 receptor showed it to be surprisingly different from the previously cloned H1 and H2 receptors, a likely explanation for the delay in its discovery. Indeed, at the time of the H3 receptor cloning, its homology to any other known G protein-coupled receptor was only 31% (Leurs et al., 2000). Because of this, the search for new receptors in a family more closely related to the H3 receptor seemed promising. As described in the accompanying articles (Liu et al., 2001; Nguyen et al., 2001; Zhu et al., 2001) and in other recent (Oda et al., 2000) and concurrent (Morse et al., 2001) articles, screening of libraries and public databases for H3-like fragments succeeded and led to the cloning and preliminary characterization of what is now referred to as the H4 receptor. This receptor is a 390-amino-acid, 7-transmembrane G protein-coupled receptor, with a 37 to 43% homology to the H3 (58% in transmembrane regions). All of the current This work was supported by Grant DA03816 from the National Institute on Drug Abuse. 0026-895X/01/5903-415–419$3.00 MOLECULAR PHARMACOLOGY Vol. 59, No. 3 Copyright © 2001 The American Society for Pharmacology and Experimental Therapeutics 816/893988 Mol Pharmacol 59:415–419, 2001 Printed in U.S.A.