Text Control of the repolarization phase of the cardiac action potential

Text Control of the repolarization phase of the cardiac action potential is critical for normal excitability. and arrhythmogenesis of a significant number of drugs (4). Accordingly there is a significant desire for the pharmacology of Kv11.1 channels and all investigational new drugs (regardless of target and mechanism(s) of action) must be tested for HERG activity before proceeding to phase-II clinical trials (5). Two kinetically unique delayed rectifier currents are active in cardiac myocytes: a rapidly activating (IKr; hERG/Kv11.1) and a slowly activating (IKs) potassium current (6). The gene underlying the latter current is usually KCNQ1 which when coexpressed with KCNE1 is responsible for the β-subunits of the?channel. Genetic defects in either of these two channels are associated with action potential prolongation arrhythmias and sudden cardiac death. Restoring repolarization to normal duration through pharmacologically increased activation of hERG is regarded as being of major clinical importance for the treatment of both acquired (e.g. drug- or chemical-induced) and genetically based prolongation of the QT interval. Compared to other voltage-gated potassium channels Kv11.1 channels have two distinguishing characteristics: gating and the molecular architecture of the pore. These unique properties of Kv11.1 channels have important implications on drug-channel interactions (4 7 The pore structure and its lability play a major role in the?promiscuous binding ability that makes it so susceptible to block by wide ranges of compounds (8). This open channel binding is usually thought to depend on inactivation of the GW0742 channel and Rabbit Polyclonal to NDUFA3. conformational changes involving specific residues lining the pore (4). The potential mechanisms by GW0742 which channel activation can be achieved are less obvious. However they generally fall into two classes i.e. those that take action by increased trafficking and retention to the cell surface (not discussed here) and those that take action more acutely by interacting with inactivation or activation processes. These Kv11.1 channel activators are grouped as Type 1 or Type 2 depending on the main effect of?the compound on Kv11.1 gating. Type-1 agonists primarily slow the rate of channel deactivation and the first member explained in this group is usually?RPR260243 (4). In contrast compounds that belong to Type 2 have a main effect that is targeted to the Kv11.1 channel inactivation process (4 7 9 It must be noted nevertheless that some Kv11.1 channel activators (e.g. “type”:”entrez-nucleotide” attrs :”text”:”KB130015″ term_id :”432072874″ term_text :”KB130015″KB130015) have mechanisms of action that preclude their classification as either Type 1 or Type 2 (observe Vandenberg et?al. (4)). A major challenge for research and clinical practice is to define what constitutes a safe way to correct prolonged repolarization in cardiac muscle mass. Drugs that increase repolarizing current by interfering with hERG inactivation also GW0742 mimic the effects of the arrhythmogenic short-QT syndrome (10) GW0742 casting some doubt on the security and efficacy of this approach. Perissinotti et?al. (2) and Guo et?al. (3) examine the molecular basis of a drug that functions by increasing current through changing the kinetics of both activation and inactivation. Whether this approach is usually safe will depend ultimately around the kinetic behavior of channel gating for drug binding to says that are only visited transiently during the cycle GW0742 of cardiac electrical events and to whether GW0742 the altered velocity of activation changes the shape (e.g. triangulation) of the action potential and its restitution properties in a safe way. This is usually no longer merely an academic exercise; new guidelines for drug screening and approval are being updated by the FDA through the comprehensive in?vitro proarrhythmic assay initiative which will require in?silico validation of mechanism and security (5). Knowledge of the gating properties of hERG and its conversation with state-dependent drugs requires appreciating this as a chemical reaction. Understanding the implications of these chemical reactions during the action potential.