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De la Rosa, V.

Publications and source records attributed to De la Rosa, V..

2 recordsLinked to original sources

TRICLOSAN IS A KCNQ3 POTASSIUM CHANNEL ACTIVATOR

KCNQ channels participate in the physiology of several cell types. In neurons of the central nervous system, the primary subunits are KCNQ2, 3 and 5. Activation of these channels silence the neurons, limiting action potential duration and preventing high-frequency action potential burst. Mutation of the KCNQ genes are associated with a wide spectrum of phenotypes characterized by hyperexcitability. Activation of KCNQ channels is an attractive strategy to treat epilepsy and other hyperexcitability conditions as are the evolution of stroke and traumatic brain injury. In this work we show that triclosan, a bactericide widely used in personal care products, activates the KCNQ3 channels but not the KCNQ2. Triclosan induces a voltage shift in the activation, increases the conductance and slows the closing of the channel. The effect is independent of PIP2. The putative binding site is located in the pore region but is distinct from the binding site for retigabine. Our results indicate that triclosan is a new activator for KCNQ channels.

biophysics

ELECTRO-STERIC MECHANISM OF CLC-2 CHLORIDE CHANNEL ACTIVATION

Two-pore voltage-gated CLC chloride channels control neuronal and muscle excitability. They share a dimeric structure but their activation mechanism remains unresolved. Here we determine the step-by-step activation mechanism of the broadly expressed CLC-2 channel using homology modelling, molecular dynamic simulations and functional studies. We establish that a two-leaf gate formed by Tyr561-H2O-Glu213 flanked by Lys568/Glu174 and Lys212 closes the canonical pore. Activation begins when a hyperpolarization-propelled intracellular chloride occupies the pore and splits Tyr561-H2O-Glu213 by electrostatic/steric repulsion. Unrestrained Glu213 rotates outwardly to bind Lys212 but the pore remains closed. Protonation breaks the Glu213-Lys212 interaction while another chloride occupies the pore thus catalysing chloride exit via Lys212. Also, we found that the canonical pore is uncoupled from a cytosolic cavity by a Tyr561-containing hydrophobic gate that prevents Glu213 protonation by intracellular protons. Our data provide atomistic details about CLC-2 activation but this mechanism might be common to other CLC channels.Competing Interest StatementThe authors have declared no competing interest.View Full Text

physiology