Identification of zebrafish histamine H1, H2 and H3 receptors and effects of histaminergic ligands on behavior
Introduction
Histamine is involved in several regulatory mechanisms in the brain, including alertness and sleep, seizure threshold, hormone secretion and pain [1], [2], [3], [4], but the detailed mechanism behind these functions are poorly established. It acts through at least four types of characterized G-protein-coupled receptors (GPCR) in mammals: histamine H1, H2, H3 and H4 receptors. Of these receptors only the H4 receptor has not been consistently found in the brain [5]. Mammalian histaminergic neurons are located in the tuberomamillary nucleus (TMN) and their fibers innervate the whole brain [6], [7], [8], supporting the concept that this is a phylogenetically well preserved system.
The histaminergic system in zebrafish resembles that of other vertebrates [9], [10]. Expression of l-histidine decarboxylase has been identified only in the caudal part of the hypothalamus in areas corresponding to the TMN in the mammalian hypothalamus [9]. Histamine H3-like receptor binding and H3-related G-protein activation have been described in the zebrafish brain [11]. However, no molecular characterization of this receptor has been done in zebrafish or any other fish species. The H1 receptor has earlier been mapped using in vivo [14C]2-deoxyglucose autoradiography and in vitro receptor-binding methods in Tilapia nilotica[12]. Recently it was shown that both zolantidine and chlorpheniramine give inhibitory avoidance responses in goldfish Carassius auratus, suggesting the potential presence of both H1 and H2 receptor in fish [13]. To date there is no evidence of the molecular identity of these receptors in fish, including the most commonly used species, zebrafish (Danio rerio). The zebrafish brain histamine content can be reduced by α-fluoromethylhistidine (α-FMH), and this reduction is associated with changes in the exploratory behavior and in T-maze performance. These changes might be due to reduced anxiety and some memory-related mechanisms after histamine depletion [14].
The gene for H1 receptor, as for several other GPCR, lacks introns [15], [16], [17], [18]. It has long been known that, in addition to the well known, important function in allergic and inflammatory conditions [19], the H1 receptor is connected to the sleep-wakefulness cycle. More recent reports suggest that the arousal effect of orexin A is due to activation of histaminergic neurotransmission mediated by H1 receptor [20], [21], [22]. The H1 receptor expression pattern in the CNS is rather widespread [23], [24]. The expression in the hypothalamus suggests the involvement in regulation of feeding, and a role in mediating the effects of leptin has been documented [25]. Activation of the H1 receptor is coupled to the stimulation of phospholipase C via Gq/11 G-proteins [26] the important transcription factor NF-κB [27].
The canine H2 receptor [28] was the first cloned intron-lacking histamine receptor. It was soon followed by the cloning of the H2 receptor from several species including human, rat and mouse [29], [30]. The H2 receptor signals through the Gs-protein, leading to stimulation of adenylyl cyclase and activation of CREB [31], [32]. The H2 receptor binding pattern has been well characterized in guinea pig brain using [125I]iodoaminopotentidine ([125I]APT) [33]. The involvement of H2 receptors in defensive/escape behavior as a response to fear has been suggested [34], [35], [36].
The histamine H3 receptor was first characterized as an autoreceptor which mediates inhibition of histamine synthesis and release [37], [38]. It is a modulator of the release of several transmitters [39], [40], [41], [42]. The cloning of H3 receptor by Lovenberg et al. [43] was followed by identification of receptor subtypes [44], [45], [46]. The H3 receptor signaling couples to the inhibitory Gi/o type of G-protein [43], [47]. The activation of H3 receptor causes an inhibition of adenylyl cyclase [43], [45]. Distinct pharmacology and expression pattern has been described for some of the isoforms of H3 receptors. The stimulation of isoforms H3A, H3B and H3C induces phosphorylation of mitogen activated protein kinase (MAPK) [45]. Recently the isoforms H3D, H3E and H3F with an alternative extracellular C terminus from rat were described [48].
The interest in the histamine receptors as drug targets has been increasing, particularly for the H3 receptor [49], [50], because histamine regulates important central functions and the receptors are abundantly expressed in important brain areas. Existing data on the zebrafish histaminergic system indicates that histamine is mostly present in the CNS of the zebrafish [9], and manipulation of histamine levels alters behavior [14]. Earlier binding studies indicate that the zebrafish has a H3-like receptor, however, no molecular biological evidence for the presence of any of the histamine receptors is available. The purpose of this study was to identify the genes for the histamine receptors, and find out if histaminergic ligands produce significant behavioral effects in developing zebrafish.
Section snippets
Experimental animals
Zebrafish (D. rerio) larvae and adults, from outbred (originate from local fish shop) and AB strains maintained in the laboratory for several generations, of both sexes were used for the study. The fish were kept at 28.5 °C with a light/dark cycle of 14 h/10 h and fed twice daily. Breeding and raising was done according to Westerfield [51]. The permit to carry out these studies was obtained from the Committee for Animal Experiments of Abo Akademi University and the Office of the Regional
Cloning and expression of zebrafish H1, H2 and H3 receptors
The zebrafish histamine receptors were cloned to provide evidence of the molecular identity. The zebrafish putative H1 receptor gene is located on chromosome 8. The intronless gene codes for a 534 aa long peptide. This is 57 aa longer than the human H1 receptor and 2 aa shorter than the predicted canine H1 receptor. The zebrafish H1 has a 20 aa extension in the 5′ end and a 12, 3 and 5 aa inserts in the intracellular loop (IC) 3 compared to human H1. The zebrafish peptide has a second methionine 17
Discussion
Cloning of the sequences for the putative H1, H2 and H3 receptors in zebrafish based on homology searches of the genbanks suggests that behavioral effects observed in fish after treatment with histamine receptor ligands are potentially mediated through specific receptors. No putative zebrafish H4 sequences were found at the time of the searches, using the human and rat H4 sequence information. No other closely related sequences were identified in the databases.
Amino acids known to be of
Acknowledgements
This work was supported by the Sigrid Juselius Foundation and the Academy of Finland. The authors are grateful to Professor Henk Timmerman and Rob Leurs for donating the drugs, to Paula Hasenson for assistance with tissue preparations and Jenny Bergqvist, Henri Koivula and Levente Bascó for help with fish keeping.
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- 1
Present address: Institute of Biomedicine/Biochemistry, Haartmaninkatu 8, 00014 University of Helsinki, Finland.
- 2
Present address: DanioLabs Ltd., Unit 7330, Cambridge Research Park, Cambridge, CB5 9TN, UK.
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Present address: Max Planck Institute of Molecular Cell Biology and Genetics, Pfotenhauerstrasse 108, 01307 Dresden, Germany.