G-protein signaling modulator 1 deficiency accelerates cystic disease in an orthologous mouse model of autosomal dominant polycystic kidney disease

Michelle Kwon, Tengis S. Pavlov, Kandai Nozu, Shauna A. Rasmussen, Daria V. Ilatovskaya, Alexandra Lerch-Gaggl, Lauren M. North, Hyunho Kim, Feng Qian, William E. Sweeney, Ellis D. Avner, Joe B. Blumer, Alexander Staruschenko, Frank Park

Research output: Contribution to journalArticle

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Abstract

Polycystic kidney diseases are the most common genetic diseases that affect the kidney. There remains a paucity of information regarding mechanisms by which G proteins are regulated in the context of polycystic kidney disease to promote abnormal epithelial cell expansion and cystogenesis. In this study, we describe a functional role for the accessory protein, G-protein signaling modulator 1 (GPSM1), also knownas activator of G-protein signaling 3, to act as a modulator of cyst progression in an orthologous mouse model of autosomal dominant polycystic kidney disease (ADPKD). A complete loss of Gpsm1 in the Pkd1V/V mouse model of ADPKD, which displays a hypomorphic phenotype of polycystin-1, demonstrated increased cyst progression and reduced renal function compared with age-matched cystic Gpsm1+/+ and Gpsm1 +/- mice. Electrophysiological studies identified a role by which GPSM1 increased heteromeric polycystin-1/polycystin-2 ion channel activity via Gβγ subunits. In summary, the present study demonstrates an important role for GPSM1 in controlling the dynamics of cyst progression in an orthologous mouse model of ADPKD and presents a therapeutic target for drug development in the treatment of this costly disease.

Original languageEnglish (US)
Pages (from-to)21462-21467
Number of pages6
JournalProceedings of the National Academy of Sciences of the United States of America
Volume109
Issue number52
DOIs
StatePublished - Dec 26 2012

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Autosomal Dominant Polycystic Kidney
GTP-Binding Proteins
Cysts
Polycystic Kidney Diseases
Kidney
Inborn Genetic Diseases
Ion Channels
Epithelial Cells
Phenotype
Pharmaceutical Preparations
Proteins

All Science Journal Classification (ASJC) codes

  • General

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G-protein signaling modulator 1 deficiency accelerates cystic disease in an orthologous mouse model of autosomal dominant polycystic kidney disease. / Kwon, Michelle; Pavlov, Tengis S.; Nozu, Kandai; Rasmussen, Shauna A.; Ilatovskaya, Daria V.; Lerch-Gaggl, Alexandra; North, Lauren M.; Kim, Hyunho; Qian, Feng; Sweeney, William E.; Avner, Ellis D.; Blumer, Joe B.; Staruschenko, Alexander; Park, Frank.

In: Proceedings of the National Academy of Sciences of the United States of America, Vol. 109, No. 52, 26.12.2012, p. 21462-21467.

Research output: Contribution to journalArticle

Kwon, M, Pavlov, TS, Nozu, K, Rasmussen, SA, Ilatovskaya, DV, Lerch-Gaggl, A, North, LM, Kim, H, Qian, F, Sweeney, WE, Avner, ED, Blumer, JB, Staruschenko, A & Park, F 2012, 'G-protein signaling modulator 1 deficiency accelerates cystic disease in an orthologous mouse model of autosomal dominant polycystic kidney disease', Proceedings of the National Academy of Sciences of the United States of America, vol. 109, no. 52, pp. 21462-21467. https://doi.org/10.1073/pnas.1216830110
Kwon, Michelle ; Pavlov, Tengis S. ; Nozu, Kandai ; Rasmussen, Shauna A. ; Ilatovskaya, Daria V. ; Lerch-Gaggl, Alexandra ; North, Lauren M. ; Kim, Hyunho ; Qian, Feng ; Sweeney, William E. ; Avner, Ellis D. ; Blumer, Joe B. ; Staruschenko, Alexander ; Park, Frank. / G-protein signaling modulator 1 deficiency accelerates cystic disease in an orthologous mouse model of autosomal dominant polycystic kidney disease. In: Proceedings of the National Academy of Sciences of the United States of America. 2012 ; Vol. 109, No. 52. pp. 21462-21467.
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AU - Kim, Hyunho

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AU - Blumer, Joe B.

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AB - Polycystic kidney diseases are the most common genetic diseases that affect the kidney. There remains a paucity of information regarding mechanisms by which G proteins are regulated in the context of polycystic kidney disease to promote abnormal epithelial cell expansion and cystogenesis. In this study, we describe a functional role for the accessory protein, G-protein signaling modulator 1 (GPSM1), also knownas activator of G-protein signaling 3, to act as a modulator of cyst progression in an orthologous mouse model of autosomal dominant polycystic kidney disease (ADPKD). A complete loss of Gpsm1 in the Pkd1V/V mouse model of ADPKD, which displays a hypomorphic phenotype of polycystin-1, demonstrated increased cyst progression and reduced renal function compared with age-matched cystic Gpsm1+/+ and Gpsm1 +/- mice. Electrophysiological studies identified a role by which GPSM1 increased heteromeric polycystin-1/polycystin-2 ion channel activity via Gβγ subunits. In summary, the present study demonstrates an important role for GPSM1 in controlling the dynamics of cyst progression in an orthologous mouse model of ADPKD and presents a therapeutic target for drug development in the treatment of this costly disease.

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