Histamine binds to the pockets of the alpha helixes of the transmembrane histamine H2 receptor. Within the phopholipid bilayer of the plasma membrane, there is a specific pocket for small lipophillic biogenic amines. Agonists (histamine) and antagonists (cimetidine) bind to the residues of the receptor within the pocket by means of nonionic and ionic molecular interaction as shown in Fig 1. 1The subtypes of histamine receptors have been established and the major subtypes include H1, H2 and H3 receptors [4].
H2 is the most important in the secretion of gastric acid from the parietal cells of the stomach and the inhibition of H2 receptors potentially reduce the production of the acid among patients suffering from peptic ulcers. These compounds that can successfully block the H2 receptors are known as the H2 receptor antagonists such as cimetidine, ranitidine, nizatidine and famotidine [5]. Mechanism of H2 Receptor Antagonist
H2 antagonists such as cimetidine competitively inhibit histamine H2 receptors with the principal aim of blocking the secretion of gastric acid regardless whether it is of nocturnal, diurnal type or even the type stimulated by foods. The structure of all H2 antagonists has a basic common characteristic and this gives them a competitive property to compete with the molecule, histamine for the active sites of H2 receptors. The principle of structure-activity relationship (SAR) has been utilized in the making of drug molecules able to block the action of compounds such as histamine which increase the production of the acid by parietal cells [4].
H2 receptor antagonists have also been used in the treatment of dyspepsia. However, latest developments have seen the H2 receptor antagonists being replaced by even more effective proton pump inhibitors Histamine (H2) Receptor Histamine H2 receptors belong to members of a large family of G-protein coupled receptors coded by a number of different genes. The expression and functionality of the members of G-protein coupled receptors family are highly regulated upon the interaction of agonists or antagonists.
Scientists have already established that H2 receptors are rapidly desensitized, down regulated and internalized with the exposure of histamine or other H2 agonists. While modulation of the function of this critical H2 receptor can lead to several insights, research on this area is still limited. In an experiment conducted on parietal cells in vitro, extended blockade of H2 receptors results into increased sensitivity of parietal cells to H2 agonists [1]. Other observations that were made include the elevated intragastric hyperacidity following an abrupt agonist withdrawal and tolerance development.
The molecular studies of the mechanism involving H2 receptors have been made possible with the advent of recombinant DNA technology which allows for cloning of individual gene and having a close study of the expression and functions of genes [6]. In general, H2 receptors show a spontaneous activity independent on histamine. Further studies on other G protein coupled receptors show that the elevated basal receptor activity independent of the agonists can be suppressed by specific antagonists known as inverse agonists.
Although overexposure of G protein coupled receptors to agonists leads to reduced gene expression of the receptors, there can be an upregulation of the receptors especially for inverse agonists. Ranitidine and Cimetidine act inversely as agonists while binding to the H2 receptor [7]. This inverse agonism displayed by ranitidine and cimetidine suggest the mechanism for the commonly made observation of the H2 antagonist-induced H2 receptor upregulation in experimental Chinese hamster ovary (CHO) cells [1].
The H2 receptors belong to the G protein-coupled receptor (GPCR) family which is also comprised of up to 800 members of membrane protein receptors. The membrane receptors have seven (7) segments spanning the cell membrane and have two termini: the amino and carboxyl termini which are essential for signal transduction. In general, the G protein coupled receptors form the largest family of signaling receptors in the entire human genome [8].