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Phosphorylation of S⁹⁵⁵ at the Protein Kinase A Consensus Promotes Maturation of the Subunit of the Colonic H⁺,K⁺-ATPase

Juan Codina^*, Jingfang Liu^*, Anthony J. Bleyer^*, Raymond B. Penn and Thomas D. DuBose, Jr.^*

^* Sections on Nephrology and Molecular Medicine, Department of Internal Medicine, Center for Human Genomics, Wake Forest University Health Sciences, Winston-Salem, North Carolina

Address correspondence to: Dr. Thomas D. DuBose, Jr., Department of Internal Medicine, Wake Forest University Health Sciences, Medical Center Boulevard, Winston-Salem, NC 27157. Phone: 336-716-2715; Fax: 336-716-2273; E-mail: tdubose{at}wfubmc.edu

Received for publication January 13, 2006. Accepted for publication April 12, 2006.

All the subunits of the Na⁺,K⁺-ATPases and H⁺,K⁺-ATPases have a protein kinase A (PKA) consensus sequence near or in the ninth transmembrane domain. The role of this domain in influencing subunit synthesis/degradation, plasma membrane localization, and ⁸⁶Rb⁺ uptake has not been established for the subunit of the colonic H⁺,K⁺-ATPase. This study examined the effect of mutating S⁹⁵⁵ (within the PKA consensus site of the subunit of the colonic H⁺,K⁺-ATPase [HK₂]) to alanine (S⁹⁵⁵/A) or aspartic acid (S⁹⁵⁵/D) on subunit expression and function. The results demonstrate that a negatively charged amino acid at position 955 of HK₂ promotes higher expression levels of both whole-cell and plasma membrane–localized HK₂. Moreover, inhibition of PKA reduced expression of wild-type HK₂ and associated ⁸⁶Rb⁺ uptake. Last, the activity of the HK₂ S⁹⁵⁵/A was rescued by treatment with 4-phenylbutyric acid, a compound that was shown previously to restore function to the cystic fibrosis transmembrane conductance regulator.

Copyright © 2008 by the American Society of Nephrology. Online ISSN: 1533-3450 Print ISSN: 1046-6673