Molecular and pharmacological characterization of the mouse histamine H3 receptor
Introduction
Histamine plays an important role in a number of physiological functions, including inflammation, gastric acid secretion, neurotransmission and immune regulation through its H1, H2, H3 and H4 receptors, respectively. Since the first cDNA cloning of the human histamine H3 receptor (Lovenberg et al., 1999), molecular characterization of histamine H3 receptors of human, guinea pig and rat have been extensively investigated Lovenberg et al., 1999, Lovenberg et al., 2000, Tardivel-lacombe et al., 2000, Drutel et al., 2000, Liu et al., 2000. These Gi-coupled presynaptic receptors from different species share high amino acid homology, yet exhibit some differences in pharmacology (Lovenberg et al., 2000). Since the advent of gene-knockout technology, the mouse has become a more important species for the evaluation of gene expressed in the brain. Our interest in the histamine H3 receptor has led us to explore the histamine H3 receptor pharmacology in the mouse.
In addition to known pharmacological variations, the existence of splice variants has been reported for rat and guinea pig Drutel et al., 2000, Tardivel-lacombe et al., 2000. Also, controversial results have also been reported for the existence of the human histamine H3 receptor splice variants Liu et al., 2000, Coge et al., 2001, Wiedemann et al., 2002, Wellendorph et al., 2002. These isoforms have been demonstrated to have distinct pharmacological properties and in some cases different tissue distribution from their corresponding “original” or “long” forms.
We have previously identified a fragment of the mouse histamine H3 receptor cDNA which was used to knockout the histamine H3 receptor mRNA expression in mice (Toyota et al., 2002). In the present study, we cloned the full length of mouse histamine H3 receptor to characterize it at both molecular and pharmacological levels and investigate whether the alternative splice variants of mouse histamine H3 receptor exist.
Section snippets
Cloning of the mouse histamine H3 receptor cDNA coding region
A 1 kb mouse histamine H3 receptor cDNA fragment was Polymerase Chain Reaction (PCR)-amplified from mouse brain cDNA (Clontech, Palo Alto, CA) using two primers [forward primer: 5′ GGC AAC GCG CTG GTC ATG CTC GCC TTC GTG 3′ (rat histamine H3 receptor coding region 151–180) and reverse primer: 5′ GGG CCC AGC AGA GCC CAA AGA TGC TCA CGA TGA 3′ (rat histamine H3 receptor coding region 1085–1118)] which were designed according to the conserved regions between the human and rat histamine H3 receptor
Comparison of the sequences of human, guinea pig, rat and mouse histamine H3 receptors
A 1 kb DNA fragment was PCR-amplified from mouse brain cDNA using two primers designed from the conserved region between the human and rat histamine H3 receptor cDNA sequences. The DNA sequence is unique and shares greater than 90% sequence identity to the human and rat histamine H3 receptor sequences, suggesting that it is a mouse histamine H3 receptor cDNA fragment. The 5′ end and 3′ end of the mouse histamine H3 receptor cDNA were PCR-amplified by RACE using mouse histamine H3 receptor
Discussion
In this study, the cloning and molecular and pharmacological characterization of the mouse histamine H3 receptor are described. The open reading frame of the mouse histamine H3 receptor mRNA encodes a 445-amino acid protein that has high homology and similar pharmacology to the rat, guinea pig and human histamine H3 receptors. The amino acid sequence analysis revealed that the seven transmembrane domains of the mouse histamine H3 receptor are identical to those of the rat histamine H3 receptor.
Acknowledgments
All of the experimental protocols comply with European Community guidelines for the use of experimental animals and have been approved by Johnson & Johnson Pharmaceutical Research and Development L.L.C IACUC.
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