Novel role for polycystin-1 in modulating cell proliferation through calcium oscillations in kidney cells

Abstract.   Objectives : Polycystin-1 (PC1), a signalling receptor regulating Ca²⁺-permeable cation channels, is mutated in autosomal dominant polycystic kidney disease, which is typically characterized by increased cell proliferation. However, the precise mechanisms by which PC1 functions on Ca²⁺ homeostasis, signalling and cell proliferation remain unclear. Here, we investigated the possible role of PC1 as a modulator of non-capacitative Ca²⁺ entry (NCCE) and Ca²⁺ oscillations, with downstream effects on cell proliferation. Results and discussion : By employing RNA interference, we show that depletion of endogenous PC1 in HEK293 cells leads to an increase in serum-induced Ca²⁺ oscillations, triggering nuclear factor of activated T cell activation and leading to cell cycle progression. Consistently, Ca²⁺ oscillations and cell proliferation are increased in PC1-mutated kidney cystic cell lines, but both abnormal features are reduced in cells that exogenously express PC1. Notably, blockers of the NCCE pathway, but not of the CCE, blunt abnormal oscillation and cell proliferation. Our study therefore provides the first demonstration that PC1 modulates Ca²⁺ oscillations and a molecular mechanism to explain the association between abnormal Ca²⁺ homeostasis and cell proliferation in autosomal dominant polycystic kidney disease.