On optimizing therapies, Orai, and ORNs

This month's installment of Generally Physiological considers individualized therapeutic strategies to treat the congenital heart condition long QT syndrome (LQTS), determination of the crystal structure of the Orai calcium channel, and nonsynaptic communication between olfactory receptor neu rons (ORNs) in insect sensilla. Defining individualized therapeutic strategies for channelopathies Mutations that lead to ion channel dysfunction can result in human chan nelopathies; however, it's difficult to determine the precise relationship between clinical phenotype and specific pathophysiological mutations or the sensitivity of disease-associated mutations to therapeutic intervention. The development of techniques whereby differentiated human cells can be reprogrammed into induced pluripotent stem cells (iPSCs) and then redifferentiated into a specific cell type holds the promise of providing a customized approach to investigating how disease causing mutations affect the cell physiology and therapeutic response of a given individual. LQTS, a congenital heart condition named for the characteristic prolongation of the QT interval seen on the electrocar-diogram (associated with delayed ventricular repolarization), can lead to syncope, arrhythmias, and sudden cardiac death. QT prolongation can be caused by a decrease in repolar-izing K + current or an increase in inward (Na + or Ca 2+) current, and LQTS can arise from mutation of any of various genes encoding cardiac ion channels or associated proteins. The most common of these mutations involves KCNQ1, KCNH2 (encoding the hERG K + channel), and SCN5A (encoding the Na v 1.5 Na + channel). Terrenoire et al. (2013) used iPSCs differentiated into cardiomyocytes (iPSC-CMs) to investigate the physiological basis for arrhythmias in a child with LQTS bearing a de novo mutation in SCN5A (F14773C) and a common polymorphism in KCNH2. Voltage-clamp analyses of iPSC-CMs from the affected child and his parents indicated that the mutation in SCN5A, associated with defective Na + channel inactivation and a consequent increase in late Na + current (I NaL)—but not the KCNH2 polymor-phism—was responsible for generating arrhythmia. Pharmacological analysis indicated that, although high concentrations of the sodium channel blocker mexiletine counteracted the pathophysiological effects of the F14773C mutation, they also inhibited current through hERG, limiting the drug's therapeutic range. Increasing stimulation frequency decreased I NaL and enhanced its reduction by mexiletine, effects consistent with the most clinically effective paradigm for controlling this individual's arrhythmia (combining mexiletine treatment with atrial pacing). Thus, the in vitro data provide a mechanistic explanation for the clinical response, and support the use of this approach to define individualized therapies …