The epithelial Ca2+ channel TRPV5 (ECaC1) plays a key role in renal and intestinal Ca2+ (re)absorption and is thus regulated by 1,25(OH)(2)D-3. The present study aims to explore whether TRPV5 is regulated by the serum and glucocorticoid inducible kinase SGK1, a kinase transcriptionally upregulated by 1,25(OH)(2)D-3. To this end cRNA encoding TRPV5 has been injected into Xenopus oocytes with or without additional injection of SGK1, its isoforms SGK2 and SGK3, constitutively active (S422D)SGK1, inactive (K127N)SGK1, constitutively active (PKB)-P-T308D,S473D and/or the Na+/H+ exchanger regulating factor NHERF2. In Xenopus laevis oocytes expression of TRPV5 increases uptake of tracer Ca2+ and induces a Ca2+ current (I-Ca). In the presence of Cl-, TRPV5 mediated Ca2+ entry leads to secondary activation of Ca2+-sensitive Cl- channels (I-Cl(Ca)). Coexpression of TRPV5 with both (S422D)SGK1 and NHERF2 stimulates tracer Ca2+ entry, I-Ca and I-Cl(Ca). The effect of (S422D)SGK1 on TRPV5 and NHERF2 expressing oocytes is mimicked by SGK1 and SGK3, but not by SGK2, constitutively active (PKB)-P-T308D,S473D or inactive (K127N)SGK1. The observations suggest that SGK1, SGK3 and NHERF2 regulate TRPV5 and are thus likely to participate in the regulation of calcium homeostasis. Copyright (C) 2004 S. Karger AG, Basel.