Loss of acidification of anterior prostate fluids in Atp12a-null mutant mice indicates that nongastric H-K-ATPase functions as proton pump in vivo

Abstract

The physiological functions of nongastric (colonic) H-K-ATPase (gene symbol Atp12a), unlike those of Na-K-ATPase and gastric H-K-ATPase, are poorly understood. It has been suggested that it pumps Na+ more efficiently than H+; however, so far, there is no direct evidence that it pumps H+ in vivo. Previously, we found that the nongastric H-K-ATPase alpha-subunit is expressed in apical membranes of rodent anterior prostate epithelium, in a complex with the Na-K-ATPase beta1-subunit. Here we report the effects of Atp12a gene ablation on polarization of the beta1-subunit and secretory function of the anterior prostate. In nongastric H-K-ATPase-deficient prostate, the Na-K-ATPase alpha-subunit resided exclusively in basolateral membranes; however, the beta1-subunit disappeared from apical membranes, demonstrating that beta1 is an authentic subunit of nongastric H-K-ATPase in vivo and that apical localization of beta1 in the prostate is completely dependent on its association with the nongastric H-K-ATPase alpha-subunit. A remarkable reduction in acidification of anterior prostate fluids was observed: pH 6.38 +/- 0.14 for wild-type mice and 6.96 +/- 0.10 for homozygous mutants. These results show that nongastric H-K-ATPase is required for acidification of luminal prostate fluids, thereby providing a strong in vivo correlate of previous functional expression studies demonstrating that it operates as a proton pump.

H-K-ATPase type 2: relevance for renal physiology and beyond

“…In benign prostate hyperplasia and prostate cancer, the HKA2 protein level is increased compared with healthy tissue but displays an altered cellular localization. By studying the prostate phenotype of HKA2-null mice, Pestov et al (68) established that HKA2 is responsible for the acidification of the anterior prostate secretion: in the absence of HKA2, its pH is 0.8 unit higher. This effect is not believed to impact the pH of the semen but could be related to the ability of rodent semen to build a plug after copulation.…”

Gastric type H+,K+-ATPase in the cochlear lateral wall is critically involved in formation of the endocochlear potential

“…For example, in the prostate of mice, the secretions are mildly acidic with a pH value of ϳ6.4. The slight acidification is, however, caused by the colonic H ϩ ,K ϩ -ATPase expressed in the prostate epithelia, because the secretions are alkalinized to pH ϳ7 when the ␣ 2 -subunit-gene is ablated (60). In kidney, although gastric type H ϩ ,K ϩ -ATPase is shown expressed in its epithelia and involved in the control of proton transport in vitro with omeprazole (17,41), in vivo application of the inhibitor to healthy human subjects did not affect their urinary pH (29,58).…”

The Putative Role of the Non-Gastric H+/K+-ATPase ATP12A (ATP1AL1) as Anti-Apoptotic Ion Transporter: Effect of the H+/K+ATPase Inhibitor SCH28080 on Butyrate-Stimulated Myelomonocytic HL-60 Cells

“…Lower expression levels were detected in the brain, placenta, lung, heart, forestomach and uterus. In rabbit brain the expression was found to be specific to the choroid plexus and cortex [14,20,21,22,23,24,25]. Functional expression of the non-gastric H + /K + ATPase alpha-subunit (HKalpha2) requires dimerization with a glycosylated beta-subunit.…”

“…In transfected MDCK cells the plasma membrane expression of human ATP1AL1 is regulated by the PKC pathway and activation of PKC leads to internalization of the H + /K + ATPase subunits [29]. The known functions of ATP12A include the regulation of acid-base and K + homeostasis in the kidney and colon, where it is expressed in the apical membranes of renal cortical collecting ducts and colon brush border [30,31,32] and the acidification of prostate secretions in the anterior lobe of the organ, where it is localized in the apical membrane of the epithelium [21,22]. In the ducts of the exocrine pancreas the non-gastric H + /K + ATPase appears to be involved in transepithelial bicarbonate secretion [33].…”