Effect of lithium on the electrical properties of polycystin-2 (TRPP2)

Abstract

Polycystin-2 (PC2, TRPP2) is a TRP-type, non-selective cation channel whose dysfunction is implicated in changes in primary cilium structure and genesis of autosomal dominant polycystic kidney disease (ADPKD). Lithium (Li⁺) is a potent pharmaceutical agent whose effect on cell function is largely unknown. In this work, we explored the effect of Li⁺ on PC2 channel function. In vitro translated PC2 was studied in a lipid bilayer reconstitution system exposed to different chemical conditions such as Li⁺ or K⁺ chemical gradients and different symmetrical concentrations of either cation. Li⁺ inhibited PC2 function only from the external side, by decreasing the single-channel conductance and modifying the reversal potential consistent with both permeability to and blockage of the channel. When a chemical gradient was imposed, the PC2 single-channel conductance was 144 pS and 107 pS for either K⁺ or Li⁺, respectively. Data were analysed in terms of the Goldman–Hodgkin–Katz approximation and energy models based on absolute rate theory to understand the mechanism(s) of Li⁺ transport and blockage of PC2. The 2S3B model better explained the findings, including saturation, anomalous mole fraction, non-linearity of the current–voltage curves under bi-ionic conditions and concentration dependence of permeability ratios. The data indicate that Li⁺ modifies PC2 channel function, whose effect unmasks a high-affinity binding site for this ion, and an intrinsic asymmetry in the pore structure of the channel. The findings provide insights into possible mechanism(s) of Li⁺ regulation of ciliary length and dysfunction mediated by this cation.