Structural Basis for Antiarrhythmic Drug Action Abstract Voltage-gated sodium (Na) channels initiate action potentials in cardiac myocytes, and they are the molecular targets for Class I antiarrhythmic drugs (AADs) used in the control of life- threatening cardiac arrhythmias. The structural basis for antiarrhythmic drug action is unknown. Na channels are large integral membrane proteins with 24 transmembrane segments. We have recently determined the crystal structure of an ancestral bacterial Na channel (NavAb) at 2.7 A resolution in a pre-open state with voltage sensors activated but the pore closed. This remarkable structure defines the structural basis for voltage sensing, pore opening and closing, and ion selectivity. Moreover, this structure reveals an entirely unexpected feature- fenestrations that lead laterally from the lipid bilayer into the pore and potentially provide an access pathway for entry of hydrophobic pore-blocking AADs to their receptor site in closed Na channels. The receptor site for antiarrhythmic drugs is located within the lumen of the pore. AADs block Na channels in rapidly firing cells more effectively because they reach their receptor site more rapidly when the pore is open. These drugs also block Na channels more effectively in damaged, depolarized cardiac myocytes because they bind with highest affinity to the inactivated state of the channel that is preferred at depolarized membrane potentials. Three different groups of Class I AADs (Ia, Ib, and Ic) modify Na channel function differentially and are useful in treatment of distinct classes of arrhythmias. Availability of the first high-resolution N channel structure now allows us to determine the structural basis for the complex blocking mechanism, use-dependence, and subclass specificity of AADs, which are essential for their clinical use. We will determine the structure of NavAb in the inactivated state, which has highest affinity for AADs. We will determine the structure of the NavAb channel with an antiarrhythmic drug bound by x-ray crystallography and define the structural basis for state-dependent drug binding. In addition, we will construct a human AAD receptor site in NavAb, determine the structure of the drug-bound, humanized Na channel, and define the structural basis for subclass-selective actions of Class Ia, Ib, and Ic AADs. These results will open a new era of Na channel pharmacology by revealing the structural basis for the state-dependent drug binding and block of this ion channel. Our results will be crucial in illuminating the structural determinants of high-affinity binding, the underlying mechanism for the complex, state- dependent access pathway of drugs to the AAD receptor site, and the structural basis for the selective binding and action of the Class Ia, Ib, and Ic AADs. This information will provide the structural basis for discovery and development of safer and more effective AADs.
Antiarrhythmic drugs are used to control life-threatening disturbances of cardiac rhythms, termed arrhythmias, but they often give incomplete control of arrhythmias or have unwanted side effects. These studies will give new, high-resolution information on the site and mechanism of action of antiarrhythmic drugs on sodium channels, their therapeutic target in the heart, which will allow design and development of improved medications for treatment of cardiac arrhythmias.
|Jiang, Daohua; Gamal El-Din, Tamer M; Ing, Christopher et al. (2018) Structural basis for gating pore current in periodic paralysis. Nature 557:590-594|
|Catterall, William A; Wisedchaisri, Goragot; Zheng, Ning (2017) The chemical basis for electrical signaling. Nat Chem Biol 13:455-463|
|Tang, Lin; Gamal El-Din, Tamer M; Swanson, Teresa M et al. (2016) Structural basis for inhibition of a voltage-gated Ca2+ channel by Ca2+ antagonist drugs. Nature 537:117-121|
|Catterall, William A; Swanson, Teresa M (2015) Structural Basis for Pharmacology of Voltage-Gated Sodium and Calcium Channels. Mol Pharmacol 88:141-50|
|Catterall, William A (2015) Regulation of Cardiac Calcium Channels in the Fight-or-Flight Response. Curr Mol Pharmacol 8:12-21|
|Chen-Izu, Ye; Shaw, Robin M; Pitt, Geoffrey S et al. (2015) Na+ channel function, regulation, structure, trafficking and sequestration. J Physiol 593:1347-60|
|Catterall, William A; Zheng, Ning (2015) Deciphering voltage-gated Na(+) and Ca(2+) channels by studying prokaryotic ancestors. Trends Biochem Sci 40:526-34|
|Catterall, William A (2014) Structure and function of voltage-gated sodium channels at atomic resolution. Exp Physiol 99:35-51|
|Gamal El-Din, Tamer M; Scheuer, Todd; Catterall, William A (2014) Tracking S4 movement by gating pore currents in the bacterial sodium channel NaChBac. J Gen Physiol 144:147-57|
|Tang, Lin; Gamal El-Din, Tamer M; Payandeh, Jian et al. (2014) Structural basis for Ca2+ selectivity of a voltage-gated calcium channel. Nature 505:56-61|
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