CaMKIIT287 and T305 regulate history‐dependent increases in α agonist–induced vascular tone

Abstract

CaMKII is a calcium and calmodulin-activated kinase that has been shown to regulate learning and memory in the brain, and contractility in blood vessels. Following Ca activation, CaMKII autophosphorylates, gaining a calcium-independent autonomous activity that reflects a molecular memory of having previously come into contact with calcium. The present study addresses whether the molecular memory properties of CaMKII are involved in the modulation of sustained vascular tone. We demonstrate a history-dependence of α agonist-induced vascular tone and show that CaMKII activation in vascular cells is also history dependent. Autophosphorylation of Thr287, which is classically associated with autonomous activity, does not persist during tone maintenance after transient increases in intracellular calcium levels. However, we have found that another site, Thr305, known from in vitro studies to be inhibitory, is regulated by α agonists in that the inhibitory action is removed, thus leading to a delayed reactivation of CaMKII as measured by Thr287 phosphorylation. By the use of a small molecule CaMKII inhibitor (KN93) as well as a decoy peptide (autoinhibitory peptide; AIP) we show a cause and effect relationship between CaMKII reactivation and sustained vascular tone maintenance. Thus, it appears that a complex interplay between the regulation of Thr305 and Thr287 provides a novel mechanism by which a history-dependence is developed and contributes to a new facet of molecular memory for CaMKII of relevance to vascular tone maintenance.

Regulation of gastrointestinal motility by Ca2+/calmodulin-stimulated protein kinase II

“…The role of CaMKII in learning and memory is strongly supported by the αCaMKII knockout mouse model [57]. A modified form of memory has been linked to a prolongation of vascular tone in vascular smooth muscle [58]. Ca 2+ /CaM dissociation from the Thr286 phosphorylated protein allows subsequent autophosphorylation at Thr305, Thr306 and Ser314 to occur [59].…”

Phosphorylation at Ser26 in the ATP-binding site of Ca2+/calmodulin-dependent kinase II as a mechanism for switching off the kinase activity

“…Thr 287 phosphorylation results in Ca 2+ -independent activity of CaMKII that persists upon the removal of Ca 2+ . Several other autophosphorylation sites have been described for CaMKII (Ser 26 , Thr 254 , Thr 262 , Ser 280 , Thr 305 , Thr 306 , Ser 319 and Ser 350 ) ([6], but see [6a], [7–9]); however, only for some of them (Thr 305 , Thr 306 and Thr 254 ) are the functional consequences known [8,10,11]. The most curious of these additional sites is Ser 26 due to its location in the ATP-binding site.…”

Regulation of CaMKII In vivo: The Importance of Targeting and the Intracellular Microenvironment

“…CaMKII is expressed most abundantly in neurons, and is involved in regulating many aspects of neuronal function, including neurotransmitter synthesis and release, modulation of ion channel activity, cellular transport, cellular morphology and neurite extension, long-term plasticity, learning, memory consolidation, and memory erasure following retrieval [2][3][4][5][6][7]. Non-neuronal CaMKII has been implicated in the regulation of other biological processes, such as fertilisation [8], osteogenic differentiation [9], and the maintenance of vascular tone [10]. Aside from its abundance in the brain, intense interest in CaMKII arose from its ability to act as autophosphorylatable molecular switch (reviewed in [11,12]).…”