CaMKIIdelta subtypes: localization and function

Charles B B Gray,Joan Heller Brown

doi:10.3389/fphar.2014.00015

Charles B B Gray, Joan Heller Brown

Open Access

https://doi.org/10.3389/fphar.2014.00015

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Abstract

In this review we discuss the localization and function of the known subtypes of calcium/calmodulin dependent protein kinase IIδ (CaMKIIδ) and their role in cardiac physiology and pathophysiology. The CaMKII holoenzyme is comprised of multiple subunits that are encoded by four different genes called CaMKIIα, β, γ, and δ. While these four genes have a high degree of sequence homology, they are expressed in different tissues. CaMKIIα and β are expressed in neuronal tissue while γ and δ are present throughout the body, including in the heart. Both CaMKIIγ and δ are alternatively spliced in the heart to generate multiple subtypes. CaMKIIδ is the predominant cardiac isoform and is alternatively spliced in the heart to generate the CaMKIIδB subtype or the slightly less abundant δC subtype. The CaMKIIδB mRNA sequence contains a 33bp insert not present in δC that codes for an 11-amino acid nuclear localization sequence. This review focuses on the localization and function of the CaMKIIδ subtypes δB and δC and the role of these subtypes in arrhythmias, contractile dysfunction, gene transcription, and the regulation of Ca2+ handling.

Highlights

Calcium/calmodulin dependent protein kinase II (CaMKII) is a multimeric enzyme consisting of distinct subunits encoded by four different genes known as CaMKIIα, β, γ, and δ
Edman and Schulman (1994) identified these same calmodulin dependent protein kinase IIδ (CaMKIIδ) subtypes in rat heart and characterized their catalytic activity and regulation by calcium-liganded calmodulin (Ca2+/CaM). They refer to the predominant cardiac subtypes as CaMKIIδB and CaMKIIδC, which correspond to the δ3 and δ2 subtypes, respectively
Further studies showed that the 11-amino acid insert in CaMKIIδB can confer nuclear localization when inserted into the variable domain of CaMKIIα and that mutagenesis of the first two lysines in the insert abrogates the nuclear localization of these constructs

Summary

EXPRESSION AND LOCALIZATION

Calcium/calmodulin dependent protein kinase II (CaMKII) is a multimeric enzyme consisting of distinct subunits encoded by four different genes known as CaMKIIα, β, γ, and δ These genes have a high degree of sequence homology but show differential tissue expression. Around the same time, Edman and Schulman (1994) identified these same CaMKIIδ subtypes in rat heart and characterized their catalytic activity and regulation by calcium-liganded calmodulin (Ca2+/CaM). They refer to the predominant cardiac subtypes as CaMKIIδB and CaMKIIδC (the convention that will be used in this review), which correspond to the δ3 and δ2 subtypes, respectively. The opposite is true: high relative expression www.frontiersin.org

Gray and Heller Brown

CONTRACTILE DYSFUNCTION