Regulation of the Epithelial Ca2+ Channel TRPV5 by the NHE Regulating Factor NHERF2 and the Serum and Glucocorticoid Inducible Kinase Isoforms SGK1 and SGK3 Expressed in Xenopus oocytes

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Abstract
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) 2D3. 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) 2D3. 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 S422DSGK1, inactive K127NSGK1, constitutively active T308D,S473DPKB and/or the Na+/H+ exchanger regulating factor NHERF2. In Xenopus laevisoocytes expression of TRPV5 increases uptake of tracer CaS422D; and induces a Ca2+ current (ICa). In the presence of Cl-, TRPV5 mediated Ca2+ entry leads to secondary activation of Ca2+-sensitive Cl- channels (ICl(Ca)). Coexpression of TRPV5 with both S422DSGK1 and NHERF2 stimulates tracer Ca2+ entry, ICa and ICl(Ca). The effect of S422DSGK1 on TRPV5 and NHERF2 expressing oocytes is mimicked by SGK1 and SGK3, but not by SGK2, constitutively active T308D,S473DPKB or inactive K127NSGK1. The observations suggest that SGK1, SGK3 and NHERF2 regulate TRPV5 and are thus likely to participate in the regulation of calcium homeostasis.

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