G-protein signaling modulator 1 deficiency accelerates cystic disease in an orthologous mouse model of autosomal dominant polycystic kidney disease. Proc Natl Acad Sci U S A 2012 Dec 26;109(52):21462-7
Date
12/14/2012Pubmed ID
23236168Pubmed Central ID
PMC3535663DOI
10.1073/pnas.1216830110Scopus ID
2-s2.0-84871834760 (requires institutional sign-in at Scopus site) 35 CitationsAbstract
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.
Author List
Kwon M, Pavlov TS, Nozu K, Rasmussen SA, Ilatovskaya DV, Lerch-Gaggl A, North LM, Kim H, Qian F, Sweeney WE Jr, Avner ED, Blumer JB, Staruschenko A, Park FAuthors
Ellis D. Avner MD Professor in the Pediatrics department at Medical College of WisconsinLauren North MD Assistant Professor in the Otolaryngology department at Medical College of Wisconsin
MESH terms used to index this publication - Major topics in bold
AnimalsCarrier Proteins
Disease Models, Animal
Disease Progression
Electrophysiological Phenomena
Fluorescent Antibody Technique
Genotype
Guanine Nucleotide Dissociation Inhibitors
Kidney
Kidney Function Tests
Mice
Polycystic Kidney, Autosomal Dominant
Protein Transport
TRPP Cation Channels
