Control of histidine decarboxylase gene expression in enterochromaffin-like cells.

The ability of histamine to stimulate gastric acid secretion was recognized over 75 years ago by Popielski [1]. The central importance of this action in the physiological regulation of acid secretion was established with the development of histamine H2 receptor antagonists by Black and colleagues in the early 1970s [2]. There has, however, been intense debate about the precise mechanisms of action, and relative importance of, histamine and the other major gastric acid secretagogues, gastrin and acetylcholine. The currently favored view proposes that gastrin and acetylcholine act principally by releasing histamine, which then acts directly on the acid-secreting parietal cell. This idea is supported by pharmacological studies on histamine H2 antagonists in vivo and in isolated perfused stomachs, and by the fact that gastrin and muscarinic agonists release histamine from the isolated perfused stomach, and increase activation of gastric histidine decarboxylase (HDC, EC 4.1.1.22), the enzyme that converts histidine to histamine [3-7]. However, there is also evidence for separate receptors for gastrin, histamine and acetylcholine on canine parietal cells [8], suggesting that in some circumstances all three agents may be able to act directly on this cell type. Kahlson and colleagues were the first to demonstrate increases in histidine decarboxylase (HDC)b activity in rodent gastric mucosa in response to gastrin and cholinergic agents [4], and it is now well recognized that this response is localized to the enterochromaffin-like (ECL) cell [4, 9, 10]. Since ECL cells represent a relatively high proportion of gastric corpus mucosal endocrine cells in rodents, these species are well suited to studies of ECL cell function. The relative scarcity ofECL cells in some other species raised questions about the generality of the gastrin-induced increases in HDC activity in this cell type [10, 11]. Nevertheless, in all species where purified ECL cells have been studied, gastrininduced activation of HDC activity has been observed [12-14]. Increases in HDC activity could, in principle, arise by de novo synthesis of enzyme, or by activation of a pre-existing but inactive enzyme pool, since it is known that HDC activity can be modulated by phosphorylation [15]. In addition, there exists the possibility that translation rates are regulated. The opportunity to examine in more detail the regulation of HDC expression arose with the cloning of a cDNA encoding the enzyme in 1990 [16], and subsequent elucidation of the genomic sequence [17, 18].