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

CANTERO, MARÍA DEL ROCÍO Y CANTIELLO, HORACIO FABIO

Los Cocos, Córdoba

Workshop; XXXVIII Reunión Anual de la Sociedad Argentina de Biofísica; 2009

SAB

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 cell surface antenna-like organelle that transduces sensory stimuli to the cell body. Dysfunctions in ciliarelated molecules 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 striatal neurons 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 in primary cilium deficiency, and the genesis of polycystic kidney disease. Herein, we explored the effect of Li+ 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-tovoltage relationships 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.