Co-assembly of polycystin-1 and -2 produces unique cation-permeable currents

Abstract

The human kidney is composed of roughly 1.2-million renal tubules that must maintain their tubular structure to function properly. In autosomal dominant polycystic kidney disease (ADPKD) cysts develop from renal tubules and enlarge independently, in a process that ultimately causes renal failure in 50% of affected individuals. Mutations in either PKD1 or PKD2 are associated with ADPKD but the function of these genes is unknown. PKD1 is thought to encode a membrane protein, polycystin-1, involved in cell-cell or cell-matrix interactions, whereas the PKD2 gene product, polycystin-2, is thought to be a channel protein. Here we show that polycystin-1 and -2 interact to produce new calcium-permeable non-selective cation currents. Neither polycystin-1 nor -2 alone is capable of producing currents. Moreover, disease-associated mutant forms of either polycystin protein that are incapable of heterodimerization do not result in new channel activity. We also show that polycystin-2 is localized in the cell in the absence of polycystin-1, but is translocated to the plasma membrane in its presence. Thus, polycystin-1 and -2 co-assemble at the plasma membrane to produce a new channel and to regulate renal tubular morphology and function.

Cell biology of polycystin-2

“…Some of the biophysical properties such as cation selectivity and regulation by Ca 2+ were in agreement with a previous study on the structurally related channel, PKD2L1 [30]. In the PKD1-PKD2 coexpression study [29], it was also shown that PKD1 facilitated the targeting of PKD2 to the plasma membrane which was necessary for channel activity. In further support of the relevance of the interaction to ADPKD, naturally occurring mutations in PKD1 or PKD2 that would eliminate their interaction resulted in loss of channel activity.…”

“…Function at the plasma membrane-Functional expression of PKD2 as an ion channel was first reported by Hanaoka et al [29]. In this study, it was demonstrated that PKD2 alone was unable to form a functional channel in CHO-K1 cells, but in association with PKD1, PKD2 displayed channel activity.…”

“…It is now accepted that PKD2 can function at the plasma membrane, but its activity there is under complex regulation involving shuttling between ER and plasma membrane, protein-protein interactions, and modes of activation. Specifically, it has been shown that the amount of PKD2 in the plasma membrane is dynamically regulated by interacting proteins (PKD1 [29,35], Polycystin-2 interactor, Golgi-and ER-associated protein-14 (PIGEA-14) [37]), posttranslational modifications (serine phosphorylation by casein kinase 2 (CK2) [38] and glycogen synthase kinase 3 (GSK3) [39]), interaction with other channel subunits in the plasma membrane (PKD1 [29,35,[40][41][42], TRPC1 [11], TRPV4 [43]) (Fig. 2), and finally, activation secondary to cell surface receptor activation (epidermal growth factor receptor (EGFR) [36]).…”

“…Interestingly, the pathogenic mutant PKD2(742X) which lacked the ER retention signal was forwarded to the plasma membrane and displayed constitutive channel activity [35,44]. However, according to Hanaoka et al this mutant did not display channel activity [29]. Nevertheless, it is possible that plasma membrane expression of PKD2 is not sufficient for function, but perhaps interactions with other subunits are needed for channel activity.…”

Ca2+ coding and decoding strategies for the specification of neural and renal precursor cells during development

“…A likely candidate is the TRPP1/TRPP2 (or polycystin-1/polycystin-2) complex [61]. The precise functions of TRPP1 and TRPP2 (transient receptor potential polycystin 1 and 2) are not completely understood, but there is growing evidence that TRPP2 might function as a Ca 2+ -regulated/Ca 2+ permeable cationic channel and that TRPP1 is a regulator or sensor of this channel [62]. TRPP1 has previously been shown to be expressed in the presumptive pronephric territory in intact Xenopus embryos and in animal caps treated with activin A and RA [63].…”