Mechanisms of CaMKII Activation in the Heart.

Jeffrey R Erickson

doi:10.3389/fphar.2014.00059

Abstract

Calcium/calmodulin (Ca2+/CaM) dependent protein kinase II (CaMKII) has emerged as a key nodal protein in the regulation of cardiac physiology and pathology. Due to the particularly elegant relationship between the structure and function of the kinase, CaMKII is able to translate a diverse set of signaling events into downstream physiological effects. While CaMKII is typically autoinhibited at basal conditions, prolonged rapid Ca2+ cycling can activate the kinase and allow post-translational modifications that depend critically on the biochemical environment of the heart. These modifications result in sustained, autonomous CaMKII activation and have been associated with pathological cardiac signaling. Indeed, improved understanding of CaMKII activation mechanisms could potentially lead to new clinical therapies for the treatment or prevention of cardiovascular disease. Here we review the known mechanisms of CaMKII activation and discuss some of the pathological signaling pathways in which they play a role.

Highlights

Calcium/calmodulin (Ca2+/CaM) dependent protein kinase II (CaMKII) has emerged as a key nodal protein in the regulation of cardiac physiology and pathology
The regulatory domain acts as a substrate for the catalytic domain within each CaMKII monomer, while adjacent regulatory domains within the multimer block both substrate and ATP binding to the catalytic domain itself (Rosenberg et al, 2005)
When CaMKII is activated by Ca2+/CaM binding in the presence of elevated [glucose], an O-GlcNAc modification is added to the regulatory domain at S280 (S279 in the alpha form), resulting in autonomous activation of the kinase (Erickson et al, 2013)

Summary

Introduction

Calcium/calmodulin (Ca2+/CaM) dependent protein kinase II (CaMKII) has emerged as a key nodal protein in the regulation of cardiac physiology and pathology. CaMKII function is critically linked to this CaM binding function of the regulatory domain; all known mechanisms of CaMKII activation require Ca2+/CaM binding as an initiating step. CaMKII has been called the “memory molecule” in part for its function in the processing of neural information from shortterm to long-term memory, and due to the ability of CaMKII to translate Ca2+ transient frequency into autonomous activation of the kinase

Results

Conclusion