cGMP Inhibition of Na+/H+ Antiporter 3 (NHE3) Requires PDZ Domain Adapter NHERF2, a Broad Specificity Protein Kinase G-anchoring Protein

Electroneutral NaCl absorption mediated by Na+/H+ exchanger 3 (NHE3) is important in intestinal and renal functions related to water/Na+ homeostasis. cGMP inhibits NHE3 in intact epithelia. However, unexpectedly it failed to inhibit NHE3 stably transfected in PS120 cells, even upon co-expression of...

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Published in:	The Journal of biological chemistry Vol. 280; no. 17; pp. 16642 - 16650
Main Authors:	Cha, Boyoung, Kim, Jae Ho, Hut, Hans, Hogema, Boris M., Nadarja, Janani, Zizak, Mirza, Cavet, Megan, Lee-Kwon, Whaseon, Lohmann, Suzanne M., Smolenski, Albert, Tse, Chung Ming, Yun, Chris, de Jonge, Hugo R., Donowitz, Mark
Format:	Journal Article
Language:	English
Published:	United States Elsevier Inc 29-04-2005 American Society for Biochemistry and Molecular Biology
Subjects:	Adenoviridae - genetics Animals Binding Sites Cell Line Cell Membrane - metabolism Cyclic AMP - metabolism Cyclic GMP - metabolism Cyclic GMP-Dependent Protein Kinase Type II Cyclic GMP-Dependent Protein Kinases - chemistry Cyclic GMP-Dependent Protein Kinases - metabolism Cytoskeletal Proteins - chemistry Cytoskeletal Proteins - metabolism Dose-Response Relationship, Drug Fibroblasts - metabolism GTP-Binding Proteins - chemistry Humans Immunoprecipitation Macromolecular Substances - metabolism Mutation Myristic Acid - chemistry Opossums Phosphoproteins Protein Binding Protein Kinases - chemistry Protein Structure, Tertiary Recombinant Fusion Proteins - metabolism Recombinant Proteins - chemistry Sodium-Hydrogen Exchanger 3 Sodium-Hydrogen Exchangers - antagonists & inhibitors Sodium-Hydrogen Exchangers - physiology Substrate Specificity Transfection
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Summary:	Electroneutral NaCl absorption mediated by Na+/H+ exchanger 3 (NHE3) is important in intestinal and renal functions related to water/Na+ homeostasis. cGMP inhibits NHE3 in intact epithelia. However, unexpectedly it failed to inhibit NHE3 stably transfected in PS120 cells, even upon co-expression of cGMP-dependent protein kinase type II (cGKII). Additional co-expression of NHERF2, the tandem PDZ domain adapter protein involved in cAMP inhibition of NHE3, restored cGMP as well as cAMP inhibition, whereas NHERF1 solely restored cAMP inhibition. In vitro conditions were identified in which NHERF2 but not NHERF1 bound cGKII. The NHERF2 PDZ2 C terminus, which binds NHE3, also bound cGKII. A non-myristoylated mutant of cGKII did not support cGMP inhibition of NHE3. Although cGKI also bound NHERF2 in vitro, it did not evoke inhibition of NHE3 unless a myristoylation site was added. These results show that NHERF2, acting as a novel protein kinase G-anchoring protein, is required for cGMP inhibition of NHE3 and that cGKII must be bound both to the plasma membrane by its myristoyl anchor and to NHERF2 to inhibit NHE3.
ISSN:	0021-9258 1083-351X
DOI:	10.1074/jbc.M500505200