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

• Published in: Proceedings of the National Academy of Sciences - PNAS 2012-12, Vol.109 (52), p.21462-21467
• Main Authors: 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
• Format: Article
• Language: English
• Subjects: Animals; Autosomal dominant polycystic kidney; Autosomal recessive polycystic kidney; Biological Sciences; Carrier Proteins - metabolism; Cellular biology; Cysts; Cytogenetics; Disease models; Disease Models, Animal; Disease Progression; Electrophysiological Phenomena; Epithelial cells; Fluorescent Antibody Technique; Genetic disorders; Genotype; Genotype & phenotype; Ion channels; Kidney - metabolism; Kidney - pathology; Kidney - physiopathology; Kidney diseases; Kidney Function Tests; Kidneys; Mice; Modulated signal processing; Polycystic kidney diseases; Polycystic Kidney, Autosomal Dominant - metabolism; Polycystic Kidney, Autosomal Dominant - pathology; Polycystic Kidney, Autosomal Dominant - physiopathology; Protein Transport; Proteins; TRPP Cation Channels - metabolism
• ISSN: 0027-8424; 1091-6490
• DOI: 10.1073/pnas.1216830110

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 known as 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 Pkd1 ⱽ/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.