Differential regulation by ATP versus ADP further links CaMKII aggregation to ischemic conditions

Vest, Rebekah S.; O’Leary, Heather; Bayer, K. Ulrich

doi:10.1016/j.febslet.2009.10.028

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Volume 583, Issue 22 , Pages 3577-3581, 19 November 2009

Differential regulation by ATP versus ADP further links CaMKII aggregation to ischemic conditions

Edited by Judit Ovádi

Department of Pharmacology, University of Colorado Denver, Mail Stop 8303, RC1-North, 12800 East 19[th] Ave., Aurora, CO 80045, United States

Received 15 July 2009; received in revised form 24 September 2009; accepted 13 October 2009. published online 19 October 2009.

Abstract

CaMKII, a major mediator of synaptic plasticity, forms extra-synaptic clusters under ischemic conditions. This study further supports self-aggregation of CaMKII holoenzymes as the underlying mechanism. Aggregation in vitro was promoted by mimicking ischemic conditions: low pH (6.8 or less), Ca²⁺ (and calmodulin), and low ATP and/or high ADP concentration. Mutational analysis showed that high ATP prevented aggregation by a mechanism involving T286 auto-phosphorylation, and indicated requirement for nucleotide binding but not auto-phosphorylation also for extra-synaptic clustering within neurons. These results clarify a previously apparent paradox in the nucleotide and phosphorylation requirement of aggregation, and support a mechanism that involves inter-holoenzyme T286-region/T-site interaction.

Keywords: Phosphorylation, CaMKII, Ischemia