title: Regulation of sodium-proton exchanger isoform 3 (NHE3) by PKA and exchange protein directly activated by cAMP (EPAC).
abstract: The Na(+)/H(+) exchanger 3 (NHE3) is expressed in the brush border membrane (BBM) of proximal tubules (PT). Its activity is down-regulated on increases in intracellular cAMP levels. The aim of this study was to investigate the contribution of the protein kinase A (PKA) and the exchange protein directly activated by cAMP (EPAC) dependent pathways in the regulation of NHE3 by adenosine 3',5'-cyclic monophosphate (cAMP). Opossum kidney cells and murine kidney slices were treated with cAMP analogs, which selectively activate either PKA or EPAC. Activation of either pathway resulted in an inhibition of NHE3 activity. The EPAC-induced effect was independent of PKA as indicated by the lack of activation of the kinase and the insensitivity to the PKA inhibitor H89. Both PKA and EPAC inhibited NHE3 activity without inducing changes in the expression of the transporter in BBM. Activation of PKA, but not of EPAC, led to an increase of NHE3 phosphorylation. In contrast, activation of PKA, but not of EPAC, inhibited renal type IIa Na(+)-coupled inorganic phosphate cotransporter (NaPi-IIa), another Na-dependent transporter expressed in proximal BBM. PKA, but not EPAC, induced the retrieval of NaPi-IIa from BBM. Our results suggest that EPAC activation may represent a previously unrecognized mechanism involved in the cAMP regulation of NHE3, whereas regulation of NaPi-IIa is mediated by PKA but not by EPAC.
authors.affiliation: Institute of Physiology, University of Zurich, Winterthurerstrasse 190, CH-8057 Zurich, Switzerland.
authors.forename: Katharina J
authors.initials: KJ
authors.lastname: Honegger
authors.forename: Paola
authors.initials: P
authors.lastname: Capuano
authors.forename: Christian
authors.initials: C
authors.lastname: Winter
authors.forename: Desa
authors.initials: D
authors.lastname: Bacic
authors.forename: Gerti
authors.initials: G
authors.lastname: Stange
authors.forename: Carsten A
authors.initials: CA
authors.lastname: Wagner
authors.forename: Jürg
authors.initials: J
authors.lastname: Biber
authors.forename: Heini
authors.initials: H
authors.lastname: Murer
authors.forename: Nati
authors.initials: N
authors.lastname: Hernando
mesh_terms: D000818:Animals; D002460:Cell Line; D000242:Cyclic AMP / Q000502:physiology*; D017868:Cyclic AMP-Dependent Protein Kinases / Q000502:physiology*; D020662:Guanine Nucleotide Exchange Factors / Q000502:physiology*; D007668:Kidney / Q000201:enzymology / Q000648:ultrastructure; D007700:Kinetics; D051379:Mice; D008871:Microvilli / Q000201:enzymology; D000074083:Sodium-Hydrogen Exchanger 3; D017923:Sodium-Hydrogen Exchangers / Q000378:metabolism*
chemical_list: C482601:Epac protein, mouse; D020662:Guanine Nucleotide Exchange Factors; C000613386:Slc9a3 protein, mouse; D000074083:Sodium-Hydrogen Exchanger 3; D017923:Sodium-Hydrogen Exchangers; D000242:Cyclic AMP; D017868:Cyclic AMP-Dependent Protein Kinases