title: Heterotrimeric G protein signaling in polycystic kidney disease.
abstract: Autosomal dominant polycystic kidney disease (ADPKD) is a signalopathy of renal tubular epithelial cells caused by naturally occurring mutations in two distinct genes, polycystic kidney disease 1 (PKD1) and 2 (PKD2). Genetic variants in PKD1, which encodes the polycystin-1 (PC-1) protein, remain the predominant factor associated with the pathogenesis of nearly two-thirds of all patients diagnosed with PKD. Although the relationship between defective PC-1 with renal cystic disease initiation and progression remains to be fully elucidated, there are numerous clinical studies that have focused upon the control of effector systems involving heterotrimeric G protein regulation. A major regulator in the activation state of heterotrimeric G proteins are G protein-coupled receptors (GPCRs), which are defined by their seven transmembrane-spanning regions. PC-1 has been considered to function as an unconventional GPCR, but the mechanisms by which PC-1 controls signal processing, magnitude, or trafficking through heterotrimeric G proteins remains to be fully known. The diversity of heterotrimeric G protein signaling in PKD is further complicated by the presence of non-GPCR proteins in the membrane or cytoplasm that also modulate the functional state of heterotrimeric G proteins within the cell. Moreover, PC-1 abnormalities promote changes in hormonal systems that ultimately interact with distinct GPCRs in the kidney to potentially amplify or antagonize signaling output from PC-1. This review will focus upon the canonical and noncanonical signaling pathways that have been described in PKD with specific emphasis on which heterotrimeric G proteins are involved in the pathological reorganization of the tubular epithelial cell architecture to exacerbate renal cystogenic pathways.
authors.affiliation: Department of Pharmaceutical Sciences, College of Pharmacy, University of Tennessee Health Science Center, Memphis, Tennessee.
authors.forename: Taketsugu
authors.initials: T
authors.lastname: Hama
authors.affiliation: Department of Pharmaceutical Sciences, College of Pharmacy, University of Tennessee Health Science Center, Memphis, Tennessee fpark@uthsc.edu.
authors.forename: Frank
authors.initials: F
authors.lastname: Park
mesh_terms: D000818:Animals; D020962:Heterotrimeric GTP-Binding Proteins / Q000235:genetics*; D006801:Humans; D009154:Mutation / Q000235:genetics; D007690:Polycystic Kidney Diseases / Q000235:genetics*; D016891:Polycystic Kidney, Autosomal Dominant / Q000235:genetics*; D015398:Signal Transduction / Q000235:genetics*; D050396:TRPP Cation Channels / Q000235:genetics
chemical_list: D020962:Heterotrimeric GTP-Binding Proteins; D050396:TRPP Cation Channels
keywords: accessory proteins; heterotrimeric G proteins; kidney; polycystic kidney disease; signal transduction