This project is concerned with a comparative analysis of ionic current channels in nerve and heart cell membranes with a particular emphasis on the effects of cardioactive drugs on both preparations. During the past year the primary experimental preparation which has been used has been the squid giant axon. The effects of lidocaine and its derivatives on the sodium ion current, I-Na, and the potassium ion current, I-K, have been studied. The mechanism by which lidocaine blocks I-K is different from the mechanism by which it blocks I-Na. Blockade of both types of channels occurs on the interior surface of the membrane, after the drug has crossed the lipid portion of the membrane. However, the sodium channel gates must open before a lidocaine molecule can reach its blocking site within the channel, whereas a potassium channel can be blocked regardless of whether or not its gates are open. This result suggests that the inner mouth of the potassium channel is accessible to drug molecules when the channel is either in its open or its closed state, whereas the inner mouth of the sodium channel is not accessible to drugs when the channel is in its closed state. This comparative analysis of I-K and I-Na is valid, in general, for most drugs. One exception is QX572, a quaternary derivative of lidocaine. The potassium channel gates must open, as is the case with the sodium channel, before blockade by this drug can occur. The QX572 molecule is about twice as long as the lidocaine molecule, which suggests that the length of a drug molecule determines whether or not a potassium channel must open before channel blockade can occur.

National Institute of Health (NIH)
National Institute of Neurological Disorders and Stroke (NINDS)
Intramural Research (Z01)
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Lake, Robert J; Grimm, Lisa M; Veraksa, Alexey et al. (2009) In vivo analysis of the Notch receptor S1 cleavage. PLoS One 4:e6728
Paydarfar, David; Forger, Daniel B; Clay, John R (2006) Noisy inputs and the induction of on-off switching behavior in a neuronal pacemaker. J Neurophysiol 96:3338-48
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