Suppression of intestinal calcium entry channel TRPV6 by OCRL, a lipid phosphatase associated with Lowe syndrome and Dent disease

Academic Article

Abstract

  • Oculocerebrorenal syndrome of Lowe (OCRL) gene product is a phosphatidyl inositol 4,5-bisphosphate [PI(4,5)P2] 5-phosphatase, and mutations of OCRL cause Lowe syndrome and Dent disease, both of which are frequently associated with hypercalciuria. Transient receptor potential, vanilloid subfamily, subtype 6 (TRPV6) is an intestinal epithelial Ca2+ channel mediating active Ca2+ absorption. Hyperabsorption of Ca2+ was found in patients of Dent disease with increased Ca2+ excretion. In this study, we tested whether TRPV6 is regulated by OCRL and, if so, to what extent it is altered by Dent-causing OCRL mutations using Xenopus laevis oocyte expression system. Exogenous OCRL decreased TRPV6-mediated Ca2+ uptake by regulating the function and trafficking of TRPV6 through different domains of OCRL. The PI(4,5)P2 5-phosphatase domain suppressed the TRPV6-mediated Ca2+ transport likely through regulating the PI(4,5)P2 level needed for TRPV6 function without affecting TRPV6 protein abundance of TRPV6 at the cell surface. The forward trafficking of TRPV6 was decreased by OCRL. The Rab binding domain in OCRL was involved in regulating the trafficking of TRPV6. Knocking down endogenous X. laevis OCRL by antisense approach increased TRPV6-mediated Ca2+ transport and TRPV6 forward trafficking. All seven Dent-causing OCRL mutations examined exhibited alleviation of the inhibitory effect on TRPV6-mediated Ca2+ transport together with decreased overall PI(4,5)P2 5-phosphatase activity. In conclusion, OCRL suppresses TRPV6 via two separate mechanisms. The disruption of PI(4,5)P2 5-phosphatase activity by Dent-causing mutations of OCRL may lead to increased intestinal Ca2+ absorption and, in turn, hypercalciuria. © 2012 the American Physiological Society.
  • Authors

    Digital Object Identifier (doi)

    Author List

  • Wu G; Zhang W; Na T; Jing H; Wu H; Peng JB
  • Volume

  • 302
  • Issue

  • 10