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(Circulation Research. 2006;99:1027.)
© 2006 American Heart Association, Inc.

Editorials

CaM Kinase Inhibition

Apply Directly to the Heart?

Barry London

From the Cardiovascular Institute, University of Pittsburgh, Pa.

Correspondence to Barry London, MD, PhD, Cardiovascular Institute, University of Pittsburgh, Scaife S572, 200 Lothrop Street, Pittsburgh, PA 15213-2582. Email londonb@upmc.edu

See related article, pages 1092–1099

Key Words: calcium • calmodulin • CaM kinase • arrhythmias • heart

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

Calcium/calmodulin-dependent protein kinases (CaM kinases) encompass a family of serine/threonine kinases (CaMKI-CaMKIV) that are regulated by calcium bound to calmodulin.^1,2 Four separate genes encode the CaMKII subunits (, ß, , ), and 6 to 12 subunits homo- or heteromultimerize to form the active enzyme. Each subunit contains an N-terminal catalytic domain which binds ATP and substrate, a regulatory domain which includes an autoinhibitory domain and a Ca/Calmodulin binding domain, and a C-terminal association (multimerization) domain. In the heart, a number of splice variants of CaMKII are expressed, including CaMKII₂ (CaMKII_C) and CaMKII₃ (CaMKII_B) which differ from each other by the presence of a nuclear localization signal between the regulatory domain and the association domain in CaMKII₃.³

CaMKII functions as a local calcium sensor in the heart. At baseline, the autoinhibitory domain prevents substrate binding to the enzyme.^1,2 In cardiac myocytes, intracellular Ca²⁺ [Ca²⁺]_i rises because of transmembrane influx through L-type Ca²⁺ channels (I_Ca) or the Na/Ca exchanger and release from internal stores such as the sarcoplasmic reticulum (SR). When intracellular Ca²⁺ rises, it binds to the EF-hand motifs at the N- and C-terminals calmodulin, an 150 amino acid ubiquitous intracellular protein. The Ca/CaM complex then binds to the regulatory domain of CaMKII and removes the inhibition of the autoinhibitory domain. Of note, activated CaMKII can be autophosphorylated at Thr287, which allows the enzyme to remain in the active state in the absence of an elevated intracellular Ca²⁺. Ultimately, dephosphorylation by intracellular phosphatases . . . [Full Text of this Article]

Related Article:

Calmodulin Kinase II Inhibition Shortens Action Potential Duration by Upregulation of K⁺ Currents

Jingdong Li, Céline Marionneau, Rong Zhang, Vaibhavi Shah, Johannes W. Hell, Jeanne M. Nerbonne, and Mark E. Anderson
Circ. Res. 2006 99: 1092-1099. [Abstract] [Full Text] [PDF]