Specific association of the gene product of <i>PKD2</i> with the TRPC1 channel

TLDR

PKD1 and PKD2 genes cause most autosomal dominant polycystic kidney disease, yet their cellular functions remain largely unknown; PKD1 encodes a large membrane protein with motifs for cell interactions, while PKD2 shares homology with PKD1 and the major subunit of voltage‑activated Ca²⁺ channels. The study aims to characterize sequence homology between PKD2 and mammalian TRPC proteins, which are activated by G protein‑coupled receptors or Ca²⁺ store depletion. The authors compare PKD2 sequences with TRPC family members to identify shared motifs and potential interaction domains. PKD2 directly associates with TRPC1 but not TRPC3, a binding mediated by distinct C‑terminal and N‑terminal domains, suggesting PKD2 may modulate TRPC‑mediated Ca²⁺ entry during GPCR activation or store depletion.

Abstract

The function(s) of the genes ( PKD1 and PKD 2) responsible for the majority of cases of autosomal dominant polycystic kidney disease is unknown. While PKD1 encodes a large integral membrane protein containing several structural motifs found in known proteins involved in cell–cell or cell–matrix interactions, PKD2 has homology to PKD1 and the major subunit of the voltage-activated Ca 2+ channels. We now describe sequence homology between PKD2 and various members of the mammalian transient receptor potential channel (TRPC) proteins, thought to be activated by G protein-coupled receptor activation and/or depletion of internal Ca 2+ stores. We show that PKD2 can directly associate with TRPC1 but not TRPC3 in transfected cells and in vitro . This association is mediated by two distinct domains in PKD2. One domain involves a minimal region of 73 amino acids in the C-terminal cytoplasmic tail of PKD2 shown previously to constitute an interacting domain with PKD1. However, distinct residues within this region mediate specific interactions with TRPC1 or PKD1. The C-terminal domain is sufficient but not necessary for the PKD2–TRPC1 association. A more N-terminal domain located within transmembrane segments S2 and S5, including a putative pore helical region between S5 and S6, is also responsible for the association. Given the ability of the TRPC to form functional homo- and heteromultimeric complexes, these data provide evidence that PKD2 may be functionally related to TRPC proteins and suggest a possible role of PKD2 in modulating Ca 2+ entry in response to G protein-coupled receptor activation and/or store depletion.