Constitutive activation of G-proteins by polycystin-1 is antagonized by polycystin-2.
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.
Delmas
Patrick
P
Wellcome Laboratory for Molecular Pharmacology, Department of Pharmacology, University College London, Gower Street, London WC1E 6BT, United Kingdom. delmas@irlnb.cnrs-mrs.fr
Nomura
Hideki
H
Li
Xiaogang
X
Lakkis
Montaha
M
Luo
Ying
Y
Segal
Yoav
Y
Fernández-Fernández
Jose M
JM
Harris
Peter
P
Frischauf
Anna-Maria
AM
Brown
David A
DA
Zhou
Jing
J
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
D006020:Glycopeptides; D020033:Protein Isoforms; C035113:polystatin; D019204:GTP-Binding Proteins