Regulation of calcium signaling by polycystin-2

Abstract

Autosomal dominant PKD (ADPKD) is a common lethal genetic disorder characterized by progressive development of fluid-filled cysts in the kidney and other target organs. ADPKD is caused by mutations in the PKD1 and PKD2 genes, encoding the transmembrane proteins polycystin-1 (PC1) and polycystin-2 (PC2), respectively. Although the function and putative interacting ligands of PC1 are largely unknown, recent evidence indicates that PC2 behaves as a TRP-type Ca 2ϩ -permeable nonselective cation channel. The PC2 channel is implicated in the transient increase in cytosolic Ca 2ϩ in renal epithelial cells and may be linked to the activation of subsequent signaling pathways. Recent studies also indicate that PC1 functionally interacts with PC2 such that the PC1-PC2 channel complex is an obligatory novel signaling pathway implicated in the transduction of environmental signals into cellular events. The present review purposely avoids issues of regulation of PC2 expression and trafficking and focuses instead on the evidence for the TRP-type cation channel function of PC2. How its role as a cation channel may unmask mechanisms that trigger Ca 2ϩ transport and regulation is the focus of attention. PC2 channel function may be essential in renal cell function and kidney development. Nonrenal-targeted expression of PC2 and related proteins, including the cardiovascular system, also suggests previously unforeseeable roles in signal transduction.kidney; autosomal dominant polycystic kidney disease; polycystin-1; transient receptor potential channels; nonselective cation channels; calcium channels THIS REVIEW PURPOSELY AVOIDS detailing regulatory aspects of polycystin-2 (PC2) trafficking and developmental expression and cellular location of the channel protein, including cell biological issues of autosomal dominant polycystic kidney disease (ADPKD), for which highly comprehensive reviews can be found (49,84,137). This review focuses instead on the description of PC2 as a channel, its structural and functional similarities with other related transient receptor potential (TRP) channels, to which family it is a recent addition, and potential roles of PC2 in Ca 2ϩ signaling. Educated guesses can be drawn insofar as PC2 function, regulation, and/or interaction with other proteins are concerned, in particular new information on the molecular interaction with PC1 and expected regulation found in other TRP channels.

Cell biology of polycystin-2

“…Subsequently, single channel studies in placental preparations [31], heterologously expressed PKD2 in Xenopus oocytes [32] and HEK293 cells [33], and in vitro translated purified PKD2 in cell-free systems [31] further characterized PKD2 activity. Despite subtle disparities among these studies [34], it was concluded that PKD2 could form a functional channel in the plasma membrane with constitutive activity upon overexpression. It allowed non-selective passing of cations, with slightly higher selectivity for Ca 2+ over Na + and K + , but higher conductance in K + [34].…”

“…Despite subtle disparities among these studies [34], it was concluded that PKD2 could form a functional channel in the plasma membrane with constitutive activity upon overexpression. It allowed non-selective passing of cations, with slightly higher selectivity for Ca 2+ over Na + and K + , but higher conductance in K + [34]. However, the high single channel conductance (100-200 pS) [24,31,35] in combination with the relatively high open probability (~20-40%) [24,31,35] did not correlate well with the moderate amplitude of whole cell currents (several hundreds pA at -100 mV) in cells overexpressing PKD2 [35,36].…”

Espins and the actin cytoskeleton of hair cell stereocilia and sensory cell microvilli

“…In this case, an increase in the hydrodynamic torque on the microvilli is believed to increase the efficiency of absorption of Na + to maintain glomerulotubular balance [56]. Kidney epithelial cells are appear to be able to sense flow via their primary cilia, deformation of which causes increases in intracellular Ca 2+ [57].…”

Emerging roles of TRPM6/TRPM7 channel kinase signal transduction complexes

“…According to primary sequence similarity, the members of the TRP gene family are classified into six subfamilies: TRPCs (seven canonical or classical TRPs), TRPVs (six vanilloid receptor and related proteins), TRPMs (eight TRP proteins homologous to the first cloned mammalian subfamily member, melastatin; Montell et al 2002a,b;Clapham et al 2003), TRPA (a single gene is present in mammalian genomes, ANKTM1; Tominaga and Caterina 2004), and two groups of more distantly related proteins, TRPMLs (three proteins defined by the initially discovered gene mucolipin 1; Slaugenhaupt 2002) and TRPPs (polycystic kidney disease 2 related proteins; Cantiello 2004). The current manuscript focuses on recent progress made in the field of TRPM cation channels.…”