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

CANTERO, MARÍA DEL ROCÍO Y CANTIELLO, HORACIO FABIO

San Francisco, California, USA

Congreso; 54th Annual Meeting - Biophysical Society; 2010

Lithium (Li+) is a potent pharmaceutical agent that has a profound effect in the treatment of bipolar affective disorder and mania. Most vertebrate cells have an immotile primary cilium, which is a cellsurface antenna-like organelle that transduces sensory stimuli to the cell body. Dysfunctions in ciliarelatedmolecules underlie the etiology of human genetic diseases such as polycystic kidney disease.Recent studies indicate that chronic Li+ treatment elongates primary cilia in neurons from the mouse central nervous system. The length of primary cilia is also increased in cultured fibroblasts and striatalneurons after treatment with Li+. We recently demonstrated that primary cilia in renal epithelial cells express polycystin-2 (PC2), a TRP-type, non-selective cation channel, whose dysfunction is implicated inprimary cilium deficiency, and the genesis of polycystic kidney disease. Herein, we explored the effect ofLi+ on PC2 channel function. Both in vitro translated and primary cilium associated-PC2 were assessed for permeability to Li+. Lipid bilayer reconstituted PC2 in the presence of either a K+ chemical gradient (150/15 mM) and increasing concentrations of Li+, or different symmetrical concentrations of either ion indicated a decreased single channel conductance, and changes in reversal potential of the current-tovoltagerelationships in the presence of Li+, consistent with both, permeability to, and a blocking effect of, Li+ on PC2 channel function. The single channel conductance in asymmetrical K+ was 160 pS, and 115 pS in asymmetrical Li+. Calculations of the reversal potentials of the fitted data with the Goldman- Hodgkin-Katz equation indicated a K+/Li+ perm-selectivity ratio of 2.0-2.2. The data are in agreement with anomalous mole-fraction properties of PC2, and the possibility that Li+ blockage of PC2 may impair its sensory function in primary cilia. The effect of Li+ on PC2 function is discussed in the context of the potential implications to ciliary length, and the genesis of ciliary-related human diseases.