Role of potassium in acid secretion

Abstract

Potassium (K+) ions are critical for the activation and catalytic cycle of the gastric H+, K(+)-ATPase, resulting in the secretion of hydrochloric acid into the parietal cell canaliculus. As both symptom, severity and esophageal mucosal damage in gastro-esophageal reflux disease (GERD) are related to the degree of acid exposure, K+ is a logical target for approaches to inhibit acid production. The probable K+ binding site on the gastric H+, K(+)-ATPase has recently been described and studies are elucidating how K+ activates the enzyme. K+ channels in the apical membrane of the parietal cell are implicated in the recycling of K+ and, to date, three potential K+ channels (KCNQ1, Kir2.1 and Kir4.1) have been identified. The channels represent theoretical sites for agents to control acid secretion but it will be difficult to develop selective blockers. An alternative strategy is to prevent K+ from activating gastric H+, K(+)-ATPase; the potassium-competitive acid blocker (P-CAB) class inhibits acid secretion by binding at or near the K+ binding site. Ongoing research is further defining the role of K+ in the functioning of the gastric H+, K(+)-ATPase, as well as determining the clinical utility of agents directed toward this important cation.

Figure 1

A simplified model for the secretion of gastric acid by the parietal cell. The H⁺,K⁺-ATPase located on the apical membrane of the parietal cell exchanges H⁺ for K⁺. K⁺ is recycled from the canaliculus into the cytoplasm by K⁺ channels in the apical membrane. The combined actions of K⁺ channels and enzymes on the basolateral membrane regulate cytoplasmic K⁺ levels. Cl^- enters the cell cytoplasm via a Cl^-/HCO₃^- exchanger and moves from the cytoplasm into the canaliculus via a Cl^- channel (most likely ClC-2).

Figure 2

Post-Albers catalytic cycle of gastric H⁺,K⁺-ATPase.