Lithium Inhibits Cation Transport in the TRP Channel Polycystin-2 (TRPP2)

CANTERO, MARÍA DEL ROCÍO Y CANTIELLO, HORACIO FABIO

Santiago de Chile, Chile

Congreso; Fetus and Placenta: A Perfect Harmony. IFPA meeting 2010; 2010

INTRODUCTION: Lithium (Li+) is a potent pharmaceutical agent that has a profound effect in the treatment of bipolar affective disorder and mania. Although Li+ is not devoid of prenatal safety concerns, and its use during lactation has been widely discouraged, it continues to be favoured by many clinicians for use during pregnancy. Nevertheless, Li+ use during late pregnancy is associated with particular clinical concerns that have not been investigated. Numerous reports of neonatal complications have been associated with Li+ treatment during late pregnancy, including cardiac dysfunction, diabetes insipidus, hypothyroidism and low muscle tone. Polycystin–2 (PC2) is a TRP-type, non-selective cation channel that permeates Ca2+ and is abundantly expressed in term human syncytiotrophoblast. We have postulated that based on its biophysical properties and regulatory mechanisms, PC2 may be an important contributor to Ca2+ delivery from the mother to the foetus. Herein, we explored the effect of Li+ on PC2 channel function. METHODS: Both in vitro translated and human syncytiotrophoblast 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. RESULTS: A decreased in the single channel conductance, and changes in reversal potential of the current-to-voltage relationships in the presence of Li+, consistent with both, permeability to, and a blocking effect of, Li+ on PC2 channel function was observed. 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 1.5-2.0. CONCLUSIONS: The data were in agreement with anomalous mole-fraction properties of PC2, and the possibility that Li+ blockage of PC2 may impair cation transport, particularly Ca2+ in the human placenta.