title: Suppression of intestinal calcium entry channel TRPV6 by OCRL, a lipid phosphatase associated with Lowe syndrome and Dent disease.
abstract: Oculocerebrorenal syndrome of Lowe (OCRL) gene product is a phosphatidyl inositol 4,5-bisphosphate [PI(4,5)P(2)] 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 Ca(2+) channel mediating active Ca(2+) absorption. Hyperabsorption of Ca(2+) was found in patients of Dent disease with increased Ca(2+) 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 Ca(2+) uptake by regulating the function and trafficking of TRPV6 through different domains of OCRL. The PI(4,5)P(2) 5-phosphatase domain suppressed the TRPV6-mediated Ca(2+) transport likely through regulating the PI(4,5)P(2) 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 Ca(2+) transport and TRPV6 forward trafficking. All seven Dent-causing OCRL mutations examined exhibited alleviation of the inhibitory effect on TRPV6-mediated Ca(2+) transport together with decreased overall PI(4,5)P(2) 5-phosphatase activity. In conclusion, OCRL suppresses TRPV6 via two separate mechanisms. The disruption of PI(4,5)P(2) 5-phosphatase activity by Dent-causing mutations of OCRL may lead to increased intestinal Ca(2+) absorption and, in turn, hypercalciuria.
authors.affiliation: Nephrology Research and Training Center, Division of Nephrology, Department of Medicine, University of Alabama at Birmingham, Birmingham, AL 35294-0006, USA.
authors.forename: Guojin
authors.initials: G
authors.lastname: Wu
authors.forename: Wei
authors.initials: W
authors.lastname: Zhang
authors.forename: Tao
authors.initials: T
authors.lastname: Na
authors.forename: Haiyan
authors.initials: H
authors.lastname: Jing
authors.forename: Hongju
authors.initials: H
authors.lastname: Wu
authors.forename: Ji-Bin
authors.initials: JB
authors.lastname: Peng
mesh_terms: D000818:Animals; D002118:Calcium / Q000378:metabolism*; D015220:Calcium Channels / Q000235:genetics / Q000378:metabolism; D057973:Dent Disease / Q000201:enzymology / Q000235:genetics / Q000378:metabolism*; D005260:Female; D055785:Gene Knockdown Techniques / Q000379:methods; D007413:Intestinal Mucosa / Q000201:enzymology / Q000378:metabolism* / Q000473:pathology; D009800:Oculocerebrorenal Syndrome / Q000201:enzymology / Q000235:genetics / Q000378:metabolism*; D010711:Phosphatidate Phosphatase / Q000235:genetics / Q000502:physiology; D010744:Phosphoric Monoester Hydrolases / Q000235:genetics / Q000502:physiology*; D011485:Protein Binding / Q000235:genetics; D021381:Protein Transport / Q000235:genetics; D051381:Rats; D050916:TRPV Cation Channels / Q000037:antagonists & inhibitors* / Q000235:genetics / Q000378:metabolism; D014982:Xenopus laevis
chemical_list: D015220:Calcium Channels; D050916:TRPV Cation Channels; C422827:TRPV6 protein, human; C112948:lipid phosphate phosphatase; D010744:Phosphoric Monoester Hydrolases; C075695:OCRL protein, human; D010711:Phosphatidate Phosphatase; D002118:Calcium