title: G-protein signaling modulator 1 deficiency accelerates cystic disease in an orthologous mouse model of autosomal dominant polycystic kidney disease.
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 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.
authors.affiliation: Division of Nephrology, Department of Medicine, Medical College of Wisconsin, Milwaukee, WI 53226, USA.
authors.forename: Michelle
authors.initials: M
authors.lastname: Kwon
authors.forename: Tengis S
authors.initials: TS
authors.lastname: Pavlov
authors.forename: Kandai
authors.initials: K
authors.lastname: Nozu
authors.forename: Shauna A
authors.initials: SA
authors.lastname: Rasmussen
authors.forename: Daria V
authors.initials: DV
authors.lastname: Ilatovskaya
authors.forename: Alexandra
authors.initials: A
authors.lastname: Lerch-Gaggl
authors.forename: Lauren M
authors.initials: LM
authors.lastname: North
authors.forename: Hyunho
authors.initials: H
authors.lastname: Kim
authors.forename: Feng
authors.initials: F
authors.lastname: Qian
authors.forename: William E
authors.initials: WE
authors.lastname: Sweeney
authors.forename: Ellis D
authors.initials: ED
authors.lastname: Avner
authors.forename: Joe B
authors.initials: JB
authors.lastname: Blumer
authors.forename: Alexander
authors.initials: A
authors.lastname: Staruschenko
authors.forename: Frank
authors.initials: F
authors.lastname: Park
mesh_terms: D000818:Animals; D002352:Carrier Proteins / Q000378:metabolism*; D004195:Disease Models, Animal; D018450:Disease Progression; D055724:Electrophysiological Phenomena; D005455:Fluorescent Antibody Technique; D005838:Genotype; D020730:Guanine Nucleotide Dissociation Inhibitors; D007668:Kidney / Q000378:metabolism / Q000473:pathology / Q000503:physiopathology; D007677:Kidney Function Tests; D051379:Mice; D016891:Polycystic Kidney, Autosomal Dominant / Q000378:metabolism* / Q000473:pathology* / Q000503:physiopathology; D021381:Protein Transport; D050396:TRPP Cation Channels / Q000378:metabolism
chemical_list: D002352:Carrier Proteins; D020730:Guanine Nucleotide Dissociation Inhibitors; D050396:TRPP Cation Channels; C498915:Gpsm1 protein, mouse