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Rhythmic
contraction of the heart is caused by the opening and closing of a plethora
of membrane-bound, ion-specific channels that conduct outward or inward
currents. Dysfunction of any one of these channels can lead to fatal
arrhythmias. The rapid (IKr) and slow (IKs) delayed rectifier K currents and the inward rectifier K current (IK1) mediate repolarization of the action potential and mutations in the genes encoding these channels (e.g., HERG, KCNQ1, KCNE1, KCNE2, KCNJ2) cause inherited forms of cardiac arrhythmia. We use site-directed mutagenesis of cloned channels and voltage clamp techniques to study the molecular basis of potassium channel dysfunction caused by these mutations. More... Voltage-gated channels such as the rapid delayed rectifier channel (hERG) open in response to membrane depolarization. In contrast, the pacemaker channel (e.g., HCN2) opens in response to membrane hyperpolarization. We are investigating the molecular mechanisms that determine the reversed polarity of the voltage sensor-activation coupling in these channels. More... The availability of cloned channels and the ease of molecular biology has enabled the elucidation of the molecular determinants of ion channel block by drugs. We are investigating the physicochemical properties of the hERG, KCNQ1 and Kv1.5 channel binding site. More... ¡@ |
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