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Journal of Physiology (2002), 540.1, p. 1
© Copyright 2002 The Physiological Society
DOI: 10.1113/jphysiol.2002.017632

K⁺ recycling and gastric acid secretion

Barry H. Hirst

Email: barry.hirst{at}ncl.ac.uk

Gastric juice contains elevated, compared with plasma, concentrations of K⁺. K⁺ is essential for the secretion of gastric acid. The molecular basis for the dependence on K⁺ is the primary proton pump, the gastric H⁺-K⁺-ATPase, the target of an important class of therapeutic agents, the proton pump inhibitors. The proton pump is localised to intracellular tubulovesicular membranes in unstimulated cells. Tubulovesicles show a low permeability to K⁺, which limits the activity of the H⁺-K⁺-ATPase in these resting cells. Upon stimulation, tubulovesicles with their cargo of H⁺-K⁺-ATPase traffic to the apical membrane (Okamato & Forte, 2001). Apical conductive pathways for K⁺ and Cl^- are co-localised with the H⁺-K⁺-ATPase in the stimulated cells (Wolosin & Forte, 1985). The ClC-2 Cl^- channel has recently been implicated as the Cl^- exit pathway, providing for HCl secretion (Sherry et al. 2001). A parallel exit pathway for K⁺ allows for apical K⁺ recycling, thereby energising the primary proton pump (Fig. 1).

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Figure 1. A simplified cellular model for the secretion of gastric acid by the parietal cell The primary proton pump uses ATP to secrete H+ in exchange for K+. Luminal K+ is maintained by apical recycling (Kir4.1 and/or KCNQ1). Net secretion of HCl is achieved by apical Cl- channels (ClC-2). Cl- enters the basal side of the cell by Cl--HCO3- exchange, which also allows the cell to discharge the excess base generated during acid secretion. A basolateral K+ recycling pathway is coupled to the basolateral Na+ pump.

Fujita et al. (2002) in this issue of The Journal of Physiology have used a range of techniques to implicate the inwardly rectifying Kir4.1 K⁺ channel in K⁺ recycling at the parietal cell apical membrane. Acid secretion was sensitive to Ba²⁺, a feature, although not a signature, of Kir channels. Kir4.1, as well as Kir4.2 and Kir7.1, were detected by RT-PCR in the gastric mucosa. Kir4.1, but not Kir4.2 or Kir7.1, was localised at the light and electron microscopic level to the parietal cell. Within the parietal cell, Kir4.1 co-localised with H⁺-K⁺-ATPase at the apical membrane. The absence of Kir4.1 from the H⁺-K⁺-ATPase-rich tubulovesicles is consistent with the impermeability of isolated tubulovesicles to K⁺, in contrast to the high K⁺ permeability of isolated apical membrane vesicles. Electrophysiological studies indicated that Kir4.1 is insensitive to external acid, at least down to pH 3.0, the limit of the experimental protocol. Thus, Kir4.1 is a strong candidate for a key component in the acid secretory process; K⁺ recycling at the apical membrane.

Kir4.1 is not the only candidate for the apical K⁺ recycling pathway. KCNQ1 has also been proposed as the key apical K⁺ recycling channel in the parietal cell (Grahammer et al. 2001). KCNQ1 mRNA and protein was identified in gastric mucosa by Northern and Western blots and immunolocalisation. Acid secretion was sensitive to the chromanol KCNQ1 inhibitor 293B, while KCNQ1 was resistant to pH 5.5 when co-expressed with KCNE3. KCNQ1 was co-localised at the light microscopic level with H⁺-K⁺-ATPase, including in the deeper parts of the parietal cells. This suggests KCNQ1 may be co-localised with H⁺-K⁺-ATPase in the K⁺-impermeable intracellular tubulovesicles, requiring a regulatory mechanism such as co-assembly with KCNE3 by protein kinase A activation to form an active K⁺ channel (Grahammer et al. 2001). The roles of Kir4.1 and KCNQ1 in K⁺ recycling at the apical membrane of the parietal cell may be complimentary. Do the K⁺ channels both subserve similar functions, but with perhaps differential regulation? Other questions require addressing. Are these apical K⁺ channels constitutively active, or regulated upon cell activation? The K⁺ and Cl^- conductive pathways in isolated parietal cell apical membranes have overlapping sensitivity to divalent captions, such as Zn²⁺ (Wolosin & Forte, 1985). ClC-2 is sensitive to Zn²⁺ (Clark et al. 1998). Do Kir4.1 and/or KCNQ1 show Zn²⁺ sensitivity? Primary parietal secretion is pH 0.8 (160 mM HCl). Can experimental protocols be devised which allow a direct demonstration that either of these channels can function at such low pH?

A cellular model for the secretion of gastric acid is now more complete (Fig. 1). K⁺ recycling at the apical membrane, coupled with the function of the H⁺-K⁺-ATPase, is paralleled by K⁺ recycling at the basolateral membrane coupled to the Na⁺-K⁺-ATPase. Expression studies, even when supported by appropriate localisation, do not always equate with physiological relevance. Thus, the experiments of Fujita et al. demonstrating that Kir4.1 is able to function in the presence of a highly acidic external environment are important. Definitive experiments indicating the involvement of Kir4.1 and/or KCNQ1 in the apical recycling of K⁺ awaits direct analysis of the apical membrane of the parietal cell. The studies of Fujita et al. provide an important insight into a serious candidate channel mediating this function.

CLARK, S., JORDT, S.-V., JENTSCH, T. J. & MATHIE, A. (1998). Journal of Physiology 506, 665-678	[Abstract/Full Text]
FUJITA, A., HORIO, Y., HIGASHI, K., MOURI, T., HATA, F., TAKEGUCHI, N. & KURACHI, Y. (2002). Journal of Physiology 540, 85-92	[Abstract/Full Text]
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This Article Abstract Full Text (PDF) All Versions of this Article: 540/1/1    most recent 2002.017632v1 Services Email this article to a friend Similar articles in this journal Similar articles in PubMed Alert me to new issues of the journal Download to citation manager Citing Articles Citing Articles via HighWire Citing Articles via Google Scholar Google Scholar Articles by Hirst, B. H. Search for Related Content PubMed PubMed Citation Articles by Hirst, B. H. Related Collections Perspectives