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(Circulation. 2008;118:2221-2222.)
© 2008 American Heart Association, Inc.

Editorial

Understanding Cardiac Calcium Channelopathies

Barry London, MD, PhD

From the Cardiovascular Institute, University of Pittsburgh, Pittsburgh, Pa.

Correspondence to Barry London, MD, PhD, Cardiovascular Institute, University of Pittsburgh Medical Center, Scaife S572, 200 Lothrop St, Pittsburgh, PA 15213–2582. E-mail londonb@upmc.edu

Key Words: Editorials • arrhythmia • calcium • channelopathies • heart defects, congenital

An extract of the first 250 words of the full text is provided, because this article has no abstract.

Timothy syndrome is a rare genetic disorder characterized by QT prolongation (designated LQT8), arrhythmias and sudden death, structural heart disease, cognitive defects with autism, syndactyly (webbed fingers and toes), hypoglycemia, and immune deficiencies.^1,2 A single mutation (G406R) in exon 8a of the cardiac L-type calcium channel (CACNA1C, Ca_v1.2, 1c) was shown to cause Timothy syndrome in multiple unrelated subjects, whereas mutations (G406R, G402S) in the alternatively spliced exon 8 (which is expressed at 3-fold–higher levels than exon 8a) cause a similar syndrome lacking syndactyly.^3,4 These 3 mutations decrease voltage-dependent inactivation of Ca_v1.2, which is predicted to slow the inactivation of I_Ca,L during each action potential, prolong action potential and QT interval duration, increase the amplitude and duration of Ca²⁺ transients, and predispose to afterdepolarizations and arrhythmias.^3–5

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Calcium/calmodulin–dependent protein kinase II (CaMKII) is a part of a family of serine/threonine kinases regulated by calcium bound to calmodulin and is encoded by 4 genes (, β, , ).^6,7 Six to 12 subunits homo- or heteromultimerize to form the active enzyme. Each subunit contains an N-terminal catalytic domain that binds ATP and substrate, a regulatory domain that includes an autoinhibitory domain, and a Ca/Calmodulin–binding domain, a C-terminal multimerization domain, and in some cases a nuclear localization signal.⁸ CaMKII functions as a local calcium sensor in the heart. In the absence of elevated intracellular Ca²⁺, the autoinhibitory domain prevents substrate binding to the enzyme. During each heartbeat, intracellular Ca²⁺ rises because of transmembrane influx through . . . [Full Text of this Article]

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