title: Constitutive activation of G-proteins by polycystin-1 is antagonized by polycystin-2.
abstract: Polycystin-1 (PC1), a 4,303-amino acid integral membrane protein of unknown function, interacts with polycystin-2 (PC2), a 968-amino acid alpha-type channel subunit. Mutations in their respective genes cause autosomal dominant polycystic kidney disease. Using a novel heterologous expression system and Ca(2+) and K(+) channels as functional biosensors, we found that full-length PC1 functioned as a constitutive activator of G(i/o)-type but not G(q)-type G-proteins and modulated the activity of Ca(2+) and K(+) channels via the release of Gbetagamma subunits. PC1 lacking the N-terminal 1811 residues replicated the effects of full-length PC1. These effects were independent of regulators of G-protein signaling proteins and were lost in PC1 mutants lacking a putative G-protein binding site. Co-expression with full-length PC2, but not a C-terminal truncation mutant, abrogated the effects of PC1. Our data provide the first experimental evidence that full-length PC1 acts as an untraditional G-protein-coupled receptor, activity of which is physically regulated by PC2. Thus, our study strongly suggests that mutations in PC1 or PC2 that distort the polycystin complex would initiate abnormal G-protein signaling in autosomal dominant polycystic kidney disease.
authors.affiliation: Wellcome Laboratory for Molecular Pharmacology, Department of Pharmacology, University College London, Gower Street, London WC1E 6BT, United Kingdom. delmas@irlnb.cnrs-mrs.fr
authors.forename: Patrick
authors.initials: P
authors.lastname: Delmas
authors.forename: Hideki
authors.initials: H
authors.lastname: Nomura
authors.forename: Xiaogang
authors.initials: X
authors.lastname: Li
authors.forename: Montaha
authors.initials: M
authors.lastname: Lakkis
authors.forename: Ying
authors.initials: Y
authors.lastname: Luo
authors.forename: Yoav
authors.initials: Y
authors.lastname: Segal
authors.forename: Jose M
authors.initials: JM
authors.lastname: Fernández-Fernández
authors.forename: Peter
authors.initials: P
authors.lastname: Harris
authors.forename: Anna-Maria
authors.initials: AM
authors.lastname: Frischauf
authors.forename: David A
authors.initials: DA
authors.lastname: Brown
authors.forename: Jing
authors.initials: J
authors.lastname: Zhou
mesh_terms: D019204:GTP-Binding Proteins / Q000378:metabolism*; D006020:Glycopeptides / Q000037:antagonists & inhibitors* / Q000378:metabolism; D006801:Humans; D007150:Immunohistochemistry; D020033:Protein Isoforms / Q000037:antagonists & inhibitors* / Q000378:metabolism
chemical_list: D006020:Glycopeptides; D020033:Protein Isoforms; C035113:polystatin; D019204:GTP-Binding Proteins