Constitutive activation of G-proteins by polycystin-1 is antagonized by polycystin-2

Patrick Delmas, Hideki Nomura, Xiaogang Li, Montaha Lakkis, Ying Luo, Yoav Segal, José M. Fernández-Fernández, Peter C Harris, Anna Maria Frischauf, David A. Brown, Jing Zhou

Research output: Contribution to journalArticle

136 Citations (Scopus)

Abstract

Polycystin-1 (PC1), a 4,303-amino acid integral membrane protein of unknown function, interacts with polycystin-2 (PC2), a 968-amino acid α-type channel subunit. Mutations in their respective genes cause autosomal dominant polycystic kidney disease. Using a novel heterologous expression system and Ca2+ and K+ channels as functional biosensors, we found that full-length PC1 functioned as a constitutive activator of Gi/o-type but not Gq-type G-proteins and modulated the activity of Ca2+ and K+ channels via the release of Gβγ 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.

Original languageEnglish (US)
Pages (from-to)11276-11283
Number of pages8
JournalJournal of Biological Chemistry
Volume277
Issue number13
DOIs
StatePublished - Mar 29 2002
Externally publishedYes

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GTP-Binding Proteins
Chemical activation
Autosomal Dominant Polycystic Kidney
Gq-G11 GTP-Binding Protein alpha Subunits
TRPP Cation Channels
RGS Proteins
Amino Acids
Mutation
polycystic kidney disease 1 protein
polycystic kidney disease 2 protein
Biosensing Techniques
G-Protein-Coupled Receptors
Protein Binding
Biosensors
Membrane Proteins
Genes
Binding Sites

ASJC Scopus subject areas

  • Biochemistry

Cite this

Constitutive activation of G-proteins by polycystin-1 is antagonized by polycystin-2. / Delmas, Patrick; Nomura, Hideki; Li, Xiaogang; Lakkis, Montaha; Luo, Ying; Segal, Yoav; Fernández-Fernández, José M.; Harris, Peter C; Frischauf, Anna Maria; Brown, David A.; Zhou, Jing.

In: Journal of Biological Chemistry, Vol. 277, No. 13, 29.03.2002, p. 11276-11283.

Research output: Contribution to journalArticle

Delmas, P, Nomura, H, Li, X, Lakkis, M, Luo, Y, Segal, Y, Fernández-Fernández, JM, Harris, PC, Frischauf, AM, Brown, DA & Zhou, J 2002, 'Constitutive activation of G-proteins by polycystin-1 is antagonized by polycystin-2', Journal of Biological Chemistry, vol. 277, no. 13, pp. 11276-11283. https://doi.org/10.1074/jbc.M110483200
Delmas, Patrick ; Nomura, Hideki ; Li, Xiaogang ; Lakkis, Montaha ; Luo, Ying ; Segal, Yoav ; Fernández-Fernández, José M. ; Harris, Peter C ; Frischauf, Anna Maria ; Brown, David A. ; Zhou, Jing. / Constitutive activation of G-proteins by polycystin-1 is antagonized by polycystin-2. In: Journal of Biological Chemistry. 2002 ; Vol. 277, No. 13. pp. 11276-11283.
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