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Voltage-gated [Na.sup.+] channels (VGSCs) are responsible for the rising phase of the action potential in excitable cells, including neurons and skeletal and cardiac myocytes. Small alterations in gating properties can lead to severe changes in cellular excitability, as evidenced by the plethora of heritable conditions attributed to mutations in VGSCs highlighting the need to better understand VGSC regulation. In this issue of the JCI, Hund et al. identify the ability of a key structural protein, [β.sub.IV-spectrin], to bind and recruit [Ca.sup.2+]/calmodulin kinase II to the channel at a cellular location key to successful action potential initiation and propagation, where it can mediate function and excitability., The [Na.sup.+] channel and disease In excitable tissues, such as muscle, heart, and nerve, action potential (AP) initiation is most often accomplished by the opening of voltage-gated [Na.sup.+] channels (VGSCs). [...]

The [Ca.sup.2+] release channel ryanodine receptor 2 (RyR2) is required for excitation-contraction coupling in the heart and is also present in the brain. Mutations in RyR2 have been linked to exercise-induced sudden cardiac death (catecholaminergic polymorphic ventricular tachycardia [CPVT]). CPVT-associated RyR2 mutations result in "leaky" RyR2 channels due to the decreased binding of the calstabin2 (FKBP12.6) subunit, which stabilizes the closed state of the channel. We found that mice heterozygous for the R2474S mutation in Ryr2 (Ryr2-R2474S mice) exhibited spontaneous generalized tonic-clonic seizures (which occurred in the absence of cardiac arrhythmias), exercise-induced ventricular arrhythmias, and sudden cardiac death. Treatment with a novel RyR2-specific compound (S107) that enhances the binding of calstabin2 to the mutant Ryr2-R2474S channel inhibited the channel leak and prevented cardiac arrhythmias and raised the seizure threshold. Thus, CPVT-associated mutant leaky Ryr2-R2474S channels in the brain can cause seizures in mice, independent of cardiac arrhythmias. Based on these data, we propose that CPVT is a combined neurocardiac disorder in which leaky RyR2 channels in the brain cause epilepsy, and the same leaky channels in the heart cause exercise-induced sudden cardiac death., Introduction Pharmacological seizure models have implicated abnormalities in intracellular [Ca.sup.2+] cycling of inhibitory interneurons and/or astrocytes as a mechanism of seizure generation (1), (2), and the inositol 1,4,5-trisphosphate receptor (IP3R), [...]

Ion channels are pore-forming proteins that provide pathways for the controlled movement of ions into or out of cells. Ionic movement across cell membranes is critical for essential and physiological processes ranging from control of the strength and duration of the heartbeat to the regulation of insulin secretion in pancreatic β cells. Diseases caused by mutations in genes that encode ion channel subunits or regulatory proteins are referred to as channelopathies. As might be expected based on the diverse roles of ion channels, channelopathies range from inherited cardiac arrhythmias, to muscle disorders, to forms of diabetes. This series of reviews examines the roles of ion channels in health and disease. [ABSTRACT FROM AUTHOR]

Long QT syndrome, a rare genetic disorder associated with life-threatening arrhythmias, has provided a wealth of information about fundamental mechanisms underlying human cardiac electrophysiology that has come about because of truly collaborative interactions between clinical and basic scientists. Our understanding of the mechanisms that control the critical plateau and repolarization phases of the human ventricular action potential has been raised to new levels through these studies, which have clarified the manner in which both potassium and sodium channels regulate this critical period of electrical activity. [ABSTRACT FROM AUTHOR]