Histamine receptors: Introduction


Histamine is an ubiquitous chemical messenger that can be released from a variety of cells (e.g. mast cells, enterochromaffin-like cells, neurones) to act on one of four histamine receptors: H1, H2, H3 and H4. The classification of histamine receptors has resulted from rigorous pharmacological analysis of the response of different isolated tissues and cells to histamine. At the present time, the four histamine receptors identified by this process have not been added to by the application of more recent cloning techniques [13-14,18,22,26-28,30,35]. Indeed, the nucleotide and protein sequences of the histamine H3 and H4 receptors have only just been elucidated. In contrast to the other histamine receptors, splice variants of the H3 and H4 receptors have been detected. There is some preliminary pharmacological evidence to suggest heterogeneity within some of the known types of histamine receptor (reviewed by the subcommittee in reference [14]), but this heterogeneity may arise from species variation [19,34], splice isoforms [29] and/or oligomerisation [4,33] and awaits the development of specific pharmacological tools.

Receptor pharmacology

The classical antihistamines (histamine H1 receptor antagonists) were developed in the early 1930s and shown to reduce the effects of histamine on many tissues, notably contraction of vascular and visceral smooth muscle. However, it became apparent that some of the effects of histamine - for example, stimulation of gastric acid secretion -- were resistant to antagonism by these compounds [24]. Application of quantitative methods to determine pA2 (-log KB) values [3] for the H1 receptor antagonist mepyramine for antagonism of histamine-stimulated contractile activity in guinea-pig ileum (H1 receptor-mediated), and the chronotropic effects of histamine in guinea-pig right atrium (H2 receptor-mediated) provided the first evidence for the presence of at least two histamine receptors [3,24]. This was confirmed by the development of selective antagonists for the H2 receptor by Sir James Black and colleagues in a classic example of rationale drug design [5-6]. Burimamide was the first compound to be described with selectivity for the H2 receptor, and a large number of more potent and selective H2 receptor antagonists have since been developed - including cimetidine, ranitidine and tiotidine [14]. Burimamide has since been shown to be a more potent antagonist of the presynaptic H3 receptor present on nerve terminals within the central and peripheral nervous systems [1-2]. Indeed this compound, and the H2 receptor agonist impromidine, provided the first evidence in mammalian brain slices for the presence of a third type of histamine receptor [2], which led to the development of selective H3 receptor agonists (e.g. R-α-methylhistamine, immetit) and antagonists (e.g. thioperamide, clobenpropit, iodoproxyfan and ciproxifan [14]. More recently, a number of groups have developed H4 selective agonists (e.g. VUF 8430) and antagonists (e.g. JNJ 7777120) which are proving invaluable to define the roles of the newest histamine receptor subtype [16,20]. There is growing evidence that both the H3 and H4 receptor are potentially exciting new therapeutic targets for neuropathological and immunological disorders, respectively, with compounds currently in Preclinical development or Phase I and II clinical trials.

Receptor signalling

Cloning techniques have identified the amino acid sequence of the human H1, H2, H3 and H4 receptors [10-11,17,22,25-28,32,35], and they are all members of the G protein-coupled receptor superfamily. The primary mechanism by which H1 receptors produce functional responses is via Gq/G11-mediated activation of phospholipase C (PLC) and Ca2+ mobilisation, whilst H2 receptors couple positively to adenylate cyclase via Gs, leading to the formation of cAMP [14]. The signal transduction pathway used by the H3 receptor appears to be via Gi and Go proteins. Thus, inhibition of forskolin-stimulated adenylate cyclase activity has been demonstrated in cells transfected with the human H3 receptor cDNA [25], although this response has not been demonstrated in native tissues. However, pertussis toxin-sensitive H3 receptor-mediated stimulation of [35S]GTPγS binding to brain membranes [7] and electrophysiological responses mediated by H3 receptors in the heart [9] have been observed. The H4 receptor regulates similar signalling mechanisms to the H3 receptor, including inhibition of adenylyl cyclase, mobilisation of calcium from intracellular stores and stimulation of MAP kinase in both heterologous expression systems and native immune cells [8,12,15,21-23,26-27,31].


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