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 Harris, Anna Maria Frischauf, David A. Brown, Jing Zhou

Research output: Contribution to journalArticle

145 Scopus citations

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

ASJC Scopus subject areas

  • Biochemistry
  • Molecular Biology
  • Cell Biology

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    Delmas, P., Nomura, H., Li, X., Lakkis, M., Luo, Y., Segal, Y., Fernández-Fernández, J. M., Harris, P., Frischauf, A. M., Brown, D. A., & Zhou, J. (2002). Constitutive activation of G-proteins by polycystin-1 is antagonized by polycystin-2. Journal of Biological Chemistry, 277(13), 11276-11283. https://doi.org/10.1074/jbc.M110483200