Calcium/calmodulin-stimulated protein kinase II (CaMKII) is a family of broad substrate specificity serine (Ser)/threonine (Thr) protein kinases widely expressed in many tissues that is capable of mediating diverse functional responses depending on its cellular and molecular microenvironment. This review briefly summarises current knowledge on the structure and regulation of CaMKII and focuses on how the molecular environment, and interaction with binding partner proteins, can produce different populations of CaMKII in different cells, or in different subcellular locations within the same cell, and how these different populations of CaMKII can produce diverse functional responses to activation following an increase in intracellular calcium concentration. This review also explores the possibility that identifying and characterising the molecular interactions responsible for the molecular targeting of CaMKII in different cells in vivo, and identifying the sites on CaMKII and/or the binding proteins through which these interactions occur, could lead to the development of highly selective inhibitors of specific CaMKII-mediated functional responses in specific cells that would not affect CaMKII-mediated responses in other cells. This may result in the development of new pharmacological agents with therapeutic potential for many clinical conditions.

In cells from the adrenal medulla, angiotensin II (AII) regulates both the activity and mRNA levels of catecholamine biosynthetic enzymes whose expression is thought to be under the control of cAMP‐responsive element (CRE) binding protein (CREB). In this study, we evaluated the effect of AII stimulation on CREB phosphorylation at Ser133 (pCREB) in bovine adrenal chromaffin cells (BACC). We found that AII produces a rapid and AII type‐1 receptor (AT1)‐dependent increase in pCREB levels, which is blocked by the MEK1/2 inhibitor U0126 but not by H‐89, SB203580 or KN‐93, suggesting that it is mediated by the extracellular‐regulated protein kinases 1 and 2 (ERK1/2) and not by cAMP‐dependent protein kinase (PKA), p38 mitogen‐activated protein kinase (p38MAPK) or Ca²⁺/calmodulin‐dependent protein kinases (CaMKs) dependent pathways. Gel‐shift experiments showed that the increase in pCREB levels is accompanied by an ERK1/2‐dependent upregulation of CRE‐binding activity. We also found that AII promotes a rapid and reversible increase in the activity of the non‐receptor tyrosine kinase Src and that the inhibition of this enzyme completely blocks the AII‐induced phosphorylation of ERK1/2, the CREB kinase _p90RSK and CREB. Our data support the hypothesis that in BACC, AII upregulates CREB functionality through a mechanism that requires Src‐mediated activation of ERK 1/2 and _p90RSK.

Different brain regions exhibit differing sensitivities to ischemia/excitotoxicity. Whether these differences are due to perfusion or intrinsic factors has not been established. Herein, we found no apparent association between sensitivity to ischemia/excitotoxicity and the level of expression or basal phosphorylation of calcium/calmodulin-stimulated protein kinase II (αCaMKII) or glutamate receptors. However, we demonstrated significant differences in CaMKII-mediated responses after ischemia/excitotoxic stimulation in striatum and cortex. In vivo ischemia and in vitro excitotoxic stimulation produced more rapid phosphorylation of Thr253-αCaMKII in striatum compared with cortex, but equal rates of Thr286-αCaMKII phosphorylation. Phosphorylation by CaMKII of Ser831-GluA1 and Ser1303-GluN2B occurred more rapidly in striatum than in cortex after either stimulus. The differences between brain regions in CaMKII activation and its effects were not accounted for by differences in the expression of αCaMKII, glutamate receptors, or density of synapses. These results implicate intrinsic tissue differences in Thr253-αCaMKII phosphorylation in the differential sensitivities of brain regions to ischemia/excitotoxicity.