Polycystin 1 (PKD1 or PC1) assembles with TRPP2 (Q86VP3) in a stoichiometry of 3TRPP2: 1PKD1, forming the receptor/ion channel complex (Yu et al., 2009). The C-terminal coiled-coil complex is critical for proper assembly (Zhu et al., 2011).  Missense mutations have been identified that affect membrane topogenesis (Nims et al. 2011). Biomarkers for polycystic kidney diseases have been identified (Hogan et al. 2015).  Extracellular divalent ions, including Ca²⁺, inhibit permeation of monovalent ions by directly blocking the TRPP2 channel pore. D643, a negatively charged amino acid in the pore, is crucial for channel permeability (Arif Pavel et al. 2016). Polycystin (TRPP/PKD) complexes, made of transient receptor potential channel polycystin (TRPP)₄ and polycystic kidney disease (PKD) proteins, play key roles in coupling extracellular stimuli with intracellular Ca²⁺ signals. PKD1 and PKD2 form a complex, the structure of which has been solved in 3-dimensions at high resolution.  The complex consists of PKD1:PKD2 = 3:1. PKD1 consists of a voltage-gated ion channel fold that interacts with PKD2 to complete a domain-swapped TRP architecture with unique features (Su et al. 2018; Su et al. 2018). The C-terminal tail of PKD1 may play a role in the prognosis of renal disease (Higashihara et al. 2018). TRPP2 uses 2 gating charges found in its fourth TMS (S4) to control its conductive state (Ng et al. 2019). Rosetta structural predictions demonstrated that the S4 undergoes approximately 3- to 5-Å transitional and lateral movements during depolarization coupled to opening of the channel pore. Both gating charges form state-dependent cation-pi interactions within the voltage sensor domain (VSD) during membrane depolarization. The transfer of a single gating charge per channel subunit is required for voltage, temperature, and osmotic swell polymodal gating. Thus, TRPP2 channel opening is dependent on activation of its VSDs (Ng et al. 2019).  Polycystin-1 assembles with K_v channels to govern cardiomyocyte repolarization and contractility (Altamirano et al. 2019). Three-dimensional in vitro models answer questions about ADPKD cystogenesis (Dixon and Woodward 2018). The polycystin-1 subunit directly contributes to the channel pore, and its eleven TMSs are sufficient for its channel function (Wang et al. 2019).  Polycystin-1 inhibits cell proliferation through phosphatase PP2A/B56alpha (Tang et al. 2019). Polycystin-1 regulates cardiomyocyte mitophagy (Ramírez-Sagredo et al. 2021). Maser and Calvet 2020 reviewed structural and functional features shared by polycystin-1 and the adhesion GPCRs (TC# 9.A.14.6.2) and discussed the implications of such similarities for our understanding of the functions of these proteins. Mutations in PKD1 and PKD2 cause autosomal dominant polycystic kidney disease (ADPKD). Polycystins are expressed in the primary cilium, and disrupting cilia structure slows ADPKD progression following inactivation of polycystins. Dysregulation of cyclin-dependent kinase 1 (Cdk1) is an early driver of cyst cell proliferation in ADPKD due to Pkd1 inactivation (Zhang et al. 2021). Genetic removal of c-Jun N-terminal kinases, Jnk1 and Jnk2, suppresses the nuclear accumulation of phospho c-Jun, reduces proliferation and reduces the severity of cystic disease. While Jnk1 and Jnk2 are thought to have largely overlapping functions, Jnk1 loss is nearly as effective as the double loss of Jnk1 and Jnk2 (Smith et al. 2021). Polycystic kidney disease (PKD), comprising autosomal dominant polycystic kidney disease (ADPKD) and autosomal recessive polycystic kidney disease (ARPKD), is characterized by incessant cyst formation in the kidney and liver. ADPKD and ARPKD represent the leading genetic causes of renal disease in adults and children, respectively. ADPKD is caused by mutations in PKD1 encoding polycystin1 (PC1) and PKD2 encoding polycystin 2 (PC2). PC1/2 are multi-pass transmembrane proteins that form a complex localized in the primary cilium. Predominant ARPKD cases are caused by mutations in polycystic kidney (Ma 2021). The mechanism of tethered agonist-mediated signaling by polycystin-1 has been investigated (Pawnikar et al. 2022). PC1 is an 11 TMS protein encoded by the PKD1 gene. It has a complex posttranslational maturation process, with over five proteolytic cleavages, and is found at multiple cellular locations. The initial description of the binding and activation of heterotrimeric Galphai/o by the juxtamembrane region of the PC1 cytosolic C-terminal tail (C-tail) opened the door tothe possibility of potential functions as a novel G protein-coupled receptor (GPCR). Subsequent  assays supported an ability of the PC1 C-tail to bind numerous members of the Galpha protein family and to either inhibit or activate G protein-dependent pathways involved in the regulation of ion channel activity, transcription factor activation, and apoptosis. PC1-mediated G protein regulation prevents kidney cyst development. Similarities between PC1 and the adhesion class of 7-TMS GPCRs, most notably a conserved GPCR proteolysis site (GPS) before the first TM domain, which undergoes autocatalyzed proteolytic cleavage, suggest potential mechanisms for PC1-mediated regulation of G protein signaling.  reviewed the evidence supporting GPCR-like functions of PC1 and their relevance to cystic disease, discusses the involvement of GPS cleavage and potential ligands in regulating PC1 GPCR function, and explores potential connections between PC1 GPCR-like activity and regulation of the channel properties of the polycystin receptor-channel complex (Maser et al. 2022). Drug targets and repurposing candidates may effectively treat pre-cystic as well as cystic ADPKD (Wilk et al. 2023).