Molecular aspects of the histamine H3 receptor
Introduction
In the historical context of histamine's pharmacology our current knowledge on the third histamine receptor has been gathered in a very short period of time. After the discovery of histamine's biological actions in 1910 [1], the first two histamine receptors were proposed in 1966 [2] and 1972 [3], based on classical pharmacological rules of drug selectivity. Using a similar strategy it was ultimately the French research group at INSERM, led by Jean-Michel Arrang and Jean-Charles Schwartz [4], which described in 1983 for the first time an additional histamine receptor, mediating a negative feedback on the release of histamine from rat brain slices.
With the rapid expansion in the knowledge on the molecular aspects of the histamine H3 receptor (H3R) following cloning of the receptor cDNA, it has been recognized as a promising G-protein coupled receptor (GPCR) target in the CNS for the treatment of a variety of diseases, e.g. obesity and cognitive disorders (for detailed reviews see [5], [6], [7], [8], [9]). Moreover, at present we are overwhelmed with a large increase in our knowledge on the molecular aspects of H3R. Especially in the last decade important new data have been generated, following the seminal paper of the Johnson & Johnson team lead by Tim Lovenberg on the cloning of the human H3R (hH3R) [10]. Despite the fact that both the histamine H1 and H2 receptor cDNA's sequences were known since the early nineties [11], [12] and substantial efforts of various laboratories to clone the H3R cDNA on the basis of homology with the other two histamine receptors, it lasted until 1999 to elucidate the molecular architecture of the hH3R [10]. Following a large scale effort to clone CNS-expressed (orphan) GPCRs, Lovenberg et al. [10] identified and subsequently ‘deorphanised’ the hH3R. The isolated hH3R cDNA encoded a 445 amino acid protein with all the hallmarks of the family A, rhodopsin-like GPCR [13], and finally confirmed initial suggestions of the GPCR nature of the H3R based on H3R agonist-induced [35S]GTPγS binding [14], [15], GTP- and PTX-sensitivity of H3R radioligand binding and/or responses [14], [16], [17].
With the identification of the hH3R cDNA, histamine receptor research was boosted a great deal and enormous progress has been made in the field ever since. The new information resulted in the identification of a novel histamine receptor, H4[18], and also evoked strong interest of many pharmaceutical companies to develop H4R selective ligands [6], [8]. Whereas the H3R has been considered by many companies as an interesting target even before 1999, the lack of molecular information and thus the availability of recombinant systems, made most companies hesitant to start drug discovery programs. A recent review by Hancock [19] on the large drug discovery efforts by Abbott Laboratories, nicely illustrates how the lack of the hH3R as a screening tool resulted in an initial setback in Abbott's H3R program. Nevertheless, their early entry in the H3R field ensured Abbott a strong position in the present H3R field [8], [19]. With the present availability of the H3R cDNA many major pharmaceutical companies have joined the search for selective and potent H3R antagonists [8]. The development of H3R ligands has recently been elaborately documented in various reviews [5], [8], [19], [20], [21].
The cloning of the H3R cDNA has also led to a detailed delineation of several molecular aspects of H3R pharmacology. With the identification of the chromosomal localization and the elucidation of the genomic H3R sequence, it became clear that the H3R gene contains various introns and, thus, alternative splicing might result in various H3R isoforms. Indeed, soon after the cloning of the hH3R cDNA, at least 20 human [22], [23], [24], [25], [26], [27], [28] and several rodent [29], [30] isoforms have been identified. In this review we present an overview of the H3R isoforms and their known signal transduction pathways for a better understanding of the mechanism of action of H3R antagonists as potential therapeutics (Fig. 1).
Section snippets
Genomic organization of the H3R
The hH3R gene is located on chromosome 20 at location 20q13.33 (HRH3 GeneID: 11255) and the coding region has been suggested to consist of either three exons and two introns (GenBank accession number AL078633) [31], or four exons and three introns [22]. Alternatively, the most 3′ intron has been proposed to be a pseudo-intron as it is retained in the hH3R(445) isoform, but deleted in the hH3R(413) isoform [23]. In the coding region for the hH3R(445) exon 1 codes for transmembrane domain (TM) 1
Identification of H3R isoforms
To date at least 20 isoforms of the hH3R are known and in addition several H3R isoforms have been identified in rat, guinea-pig and mouse as well [22], [23], [24], [28], [29], [30], [31], [37], [40], [41]. So far no isoforms were found for the monkey H3R [39]. The complete spectrum of H3R isoforms might be highly species-specific, complicating the evaluation of the various isoforms in relation to the effectiveness of H3R ligands in vivo.
For the hH3R, alternative splicing occurs in four
Inhibition of adenylyl cyclase
Early experiments studying the receptor function employing pertussis toxin (PTX) using various assay systems, such as AtT-20 cells endogenously expressing the H3R [17], the guinea pig atria [42] and modulation of the H3R induced [35S]-GTPγS binding in rat brain [43], suggested that the H3R might be Gαi/o-coupled [14]. Expression of the cloned H3R cDNA in SK-N-MC cells confirmed the linkage of the hH3R to Gαi/o-proteins by showing its ability to inhibit the forskolin induced cAMP formation in a
Expression of the H3R isoforms
The initial cloning of the hH3R gene demonstrated that the full length receptor is a hH3R(445) amino acid G-protein coupled receptor that is found almost exclusively in the brain [10]. Whether the so far described isoforms indeed play an important role will depend on their expression levels and potential differential expression. Cogé et al. [22] showed by Northern blots analysis a high signal for the hH3R(445) in thalamus, caudate nucleus, putamen and cerebellum, a lower signal in the amygdala
Pharmacological characteristics of H3R isoforms
Pharmacological characterization of different hH3R isoforms have been described in two publications (Table 1). Of the six isoforms cloned by Cogé et al. [22], three isoforms (hH3R(445), hH3R(431), hH3R(365)) were expressed in CHO cells and pharmacologically characterized, with a focus on the hH3R(445) and hH3R(365). The hH3R(431), which lacks 14 amino acids at the C-terminal end of TM2, showed no [125I]Iodoproxyfan radioligand binding. Whereas this deletion does not affect the key-residues in
Dimerization of H3Rs
The concept of GPCR dimerization is now well documented in literature (for detailed reviews see [98]), and such direct protein–protein interactions between different GPCRs are suggested to allow a whole vista of possibilities for subtle changes in the pharmacology of these GPCRs from their monomeric, homo-dimeric or -oligomeric entities, which were previously attributed to the existence of additional receptor subtypes. In view of the recent discovery of H3R isoforms, which are often
Concluding remarks
The cloning of the hH3R has led to the discovery of several signal transduction pathways that are modulated by the hH3R. Some of these signaling pathways can be linked to relevant pathophysiologies. The hH3R-mediated inhibition of the NHE leads to a subsequent lowering in the exocytosis of norepinephrine and thereby providing an explanation for the protective role of hH3R agonists during myocardial ischemia. The cloning of the receptor gene resulted in the elucidation of the genomic
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Current address: Boehringer Ingelheim Pharma GmbH & Co. KG, Biberach, Germany.