Effect of lithium on the electrical properties of polycystin-2 (TRPP2)
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 un...
| Autores: | , |
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| Tipo de recurso: | artículo |
| Estado: | Versión publicada |
| Fecha de publicación: | 2011 |
| País: | Argentina |
| Institución: | Consejo Nacional de Investigaciones Científicas y Técnicas |
| Repositorio: | CONICET Digital (CONICET) |
| Idioma: | inglés |
| OAI Identifier: | oai:ri.conicet.gov.ar:11336/13327 |
| Acceso en línea: | http://hdl.handle.net/11336/13327 |
| Access Level: | acceso abierto |
| Palabra clave: | Lithium Pc2 Primary Cilia https://purl.org/becyt/ford/3.3 https://purl.org/becyt/ford/3 |
| Sumario: | 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. |
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