1.A.5 The Polycystin Cation Channel (PCC) Family
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 kidneys 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 and hepatic disease 1 (PKHD1) gene that encodes the Fibrocystin/Polyductin (FPC) protein, whereas a small subset of cases are caused by mutations in DAZ interacting zinc finger protein 1 like (DZIP1L) gene (Ma 2021). Probenecid slows disease progression in a murine model of autosomal dominant polycystic kidney disease (Arkhipov et al. 2023). PKD2/polycystin-2 inhibits LPS-induced acute lung injury by activating autophagy (Pan et al. 2023).
Human polycystin 1 (PC1) is a huge protein of 4303 aas. Its repeated leucine-rich (LRR) segment is found in many proteins. According to the SwissProt description, polycystin 1 contains 16 polycystic kidney disease (PKD) domains, one LDL-receptor class A domain, one C-type lectin family domain, and 16-18 putative TMSs in positions between residues 2200 and 4100. However, atomic force microscopy imaging has revealed the domain structure of polycystin-1 (Oatley et al., 2012). It exhibits minimal sequence similarities, but similar domain organization and membrane topology with established cation channels such as the transient receptor potential (TRP) and voltage-gated ion channel (VIC) family proteins (TC#s 1.A.4 and 1.A.1, respectively). However, PSI-BLAST without iterations does not pick up these similarities. The PKD2L1-PKD1L3 complex perceives sour taste. Disruption of the PKD2-PKD1 complex, responsible for mechanosensation, leads to development of ADPKD (autosomal-dominant polycystic kidney disease) (Dalagiorgou et al. 2010). Polycystic kidney disease is an inherited degenerative disease in which the uriniferous tubules are replaced by expanding fluid-filled cysts that ultimately destroy organ function (Smith et al. 2021).
Besides modulating channel activity and related signalling events, the CRDs (C-terminal regulatory domains) of PKD2 and PKD2L1 play a central role in channel oligomerization. These proteins appear to form trimers (Molland et al. 2010). Polycystin-1 is a possible receptor, able to sense extracellular stiffness and to negatively control the cellular actomyosin contraction machinery. Nigro and Boletta 2021 reviewed the literature on autosomal dominant polycystic kidney disease, providing a mechanistic view on the topic. Liu et al. 2023 discussed the characteristics of polycystins in the context of cilia and summarize the functions of mastigonemes in unicellular ciliates. They further compare eukaryotic flagella and molecular features of PC-2 between unicellular and multicellular organisms, with the aim of providing new insights into the ciliary roles of polycystins in general.
Polycystin-L has been shown to be a cation (Na+, K+ and Ca2+) channel that is activated by Ca2+, while polycystin-2 has been characterized as a Ca2+-permeable cation-selective channel. Two members of the PCC family (polycystin 1 and 2; PKD1 and 2) are mutated in human autosomal dominant polycystic kidney disease, and polycystin-L, very similar and probably orthologous to PKD2, is deleted in mice with renal and retinal defects. PKD1 and 2 interact to form the non-selective cation channel in vitro, but PKD2 can form channels in the absence of any other associated protein. Polycystin-2 transports a variety of organic cations (dimethylamine, tetraethylammonium, tetrabutylammonium, tetrapropylammonium, tetrapentenyl ammonium). The channel diameter was estimated to be at least 1.1 Å (Anyatonwu and Ehrlich, 2005). Both are reported to be integral membrane proteins with 7-11 TMSs (PKD1) and 6 TMSs (PKD2), respectively. They share a homologous region of about 400 residues (residues 206-623 in PKD2; residues 3656-4052 in PKD1) which includes five TMSs of both proteins. This may well be the channel domain. PKD2 and polycystin-L have been shown to exhibit voltage-, pH- and divalent cation-dependent channel activity (Gonzalez-Perrett et al., 2002; Liu et al., 2002). PKD1 may function primarily in regulation, both activating and stabilizing the polycystin-2 channel (Xu et al., 2003).
Autosomal recessive polycystic kidney disease is caused by mutations in PKHD1, which encodes the membrane-associated receptor-like protein fibrocystin/polyductin (FPC) (Q8TCZ9, 4074aaa). FPC associates with the primary cilia of epithelial cells and co-localizes with the Pkd2 gene product polycystin-2 (PC2; TRPP2). Kim et al. (2008) have concluded that a functional and molecular interaction exists between FPC and PC2 in vivo. Mutations in polycystin-1 and transient receptor potential polycystin 2 (TRPP2) account for almost all clinically identified cases of autosomal dominant polycystic kidney disease (ADPKD), one of the most common human genetic diseases. TRPP2 functions as a cation channel in its homomeric complex and in the TRPP2/polycystin-1 receptor/ion channel complex (Arif Pavel et al. 2016).
Humans have five PKD1 proteins, whereas sea urchins have 10. The PKD1 proteins of the sea urchin, Strongylocentrotus purpuratus, are referred to as the Receptor for Egg Jelly, or SpREJ proteins. SpREJ proteins form a subfamily within the PKD1 family. They frequently contain C-type lectin domains, PKD repeats, a REJ domain, a GPS domain, a PLAT/LH2 domain, 1-11 transmembrane segments and a C-terminal coiled-coil domain. SpREJs show distinct patterns of expression during embryogenesis, and adult tissues show tissue-specific patterns of SpREJ expression (Gunaratne et al. 2007).
The TRP-ML1 protein (Mucolipin-1) has been shown to be a lysosomal monovalent cation channel that undergoes inactivating proteolytic cleavage (Kiselyov et al., 2005). It shows greater sequence similarity to the transmembrane region of polycystin 2 than it does to members of the TRP-CC family (1.A.4). Therefore, it is included in the former family. Both the PCC and TRP-CC families are members of the VIC superfamily.
Transient receptor potential (TRP) polycystin 2 and 3 (TRPP2 and 3) are homologous members of the TRP superfamily of cation channels but have different physiological functions. TRPP2 is part of a flow sensor, and is defective in autosomal dominant polycystic kidney disease and implicated in left-right asymmetry development. TRPP3 is implicated in sour tasting in bipolar cells of taste buds of the tongue and in the regulation of pH-sensitive action potential in neurons surrounding the central canal of the spinal cord. TRPP3 is present in both excitable and non-excitable cells in various tissues, such as retina, brain, heart, testis, and kidney.
Alpha-actinin is an actin-bundling protein known to regulate several types of ion channels. Planer lipid bilayer electrophysiology showed that TRPP3 exhibits cation channel activities that are substantially augmented by alpha-actinin. The TRPP3-alpha-actinin association was documented by co-immunoprecipitation using native cells and tissues, yeast two-hybrid, and in vitro binding assays (Li et al., 2007). TRPP3 is abundant in mouse brain where it associates with alpha-actinin-2. Alpha-actinin attaches TRPP3 to the cytoskeleton and up-regulates its channel function.
Renal cysts, which arise from renal tubules, can be seen in a variety of hereditary and nonhereditary entities. Common mechanisms associated with renal cyst formation include increased cell proliferation, epithelial fluid secretion, and extracellular matrix remodeling (Ghata and Cowley 2017). Hereditary polycystic kidney disease (PKD) is seen as a component of numerous diseases. Autosomal dominant (AD) PKD is the most common potentially fatal hereditary disease in humans, causes renal failure in approximately 50% of affected individuals, and accounts for approximately 5% of end stage renal disease cases in the United States. ADPKD is caused by mutation in one of two genes-85% of cases are caused by mutation in PKD1 on chromosome 16, and 15% of cases are caused by mutation in PKD2 on chromosome 4. Polycystin-1, encoded by PKD1, is a large protein, has multiple transmembrane spanning domains, has extracellular regions suggesting a role in cell-cell or cell-matrix interactions, has intracellular domains suggesting a role in signal transduction, and can physically interact with Polycystin-2. Polycystin-2 is smaller, has transmembrane domains, can act as a cation channel with calcium permeability, and may be regulated by Polycystin-1. These proteins, and many others associated with cystic kidney disease, localize to primary cilia, which may act as flow sensors in the kidney; cystic kidney diseases have also been termed ciliopathies (Ghata and Cowley 2017).
Mutations in polycystin-1 (PC1) and PC2 result in ADPKD, characterized by the formation and development of kidney cysts as has been reviewed by Lemos and Ehrlich 2017. Epithelial cells with loss-of-function of PC1 or PC2 show higher rates of proliferation and apoptosis and reduced autophagy. PC1 serves as a sensor that is usually found in complex with PC2, the calcium-permeable cation channel of the system. In addition to decreased Ca2+ signaling, several other cell fate-related pathways are de-regulated in ADPKD, including cAMP, MAPK, Wnt, JAK-STAT, Hippo, Src, and mTOR. In their review, Lemos and Ehrlich 2017 discuss how polycystins regulate cell death and survival, highlighting the complexity of molecular cascades that are involved in ADPKD. Canonical and noncanonical signaling pathways have been reviewed with emphasis on which heterotrimeric G proteins are involved in the pathological reorganization of the tubular epithelial cell architecture to exacerbate renal cystogenic pathways (Hama and Park 2016).
PC1, PC2 and fibrocystin proteins, the respective products of the PKD1, PKD2 and PKHD1 genes, are abundant in urinary exosome-like vesicles (ELVs) where they form the polycystin complex (PCC). ELVs are 100 nm diameter membrane vesicles shed into the urine by the cells lining the nephron (Lea et al. 2020). The three major human cystogene proteins are detectable in human urinary ELVs and that all three undergo post-translational proteolytic processing (Lea et al. 2020).
PCC proteins catalyze:
Cations (in) 
Cations (out)