Camguk Regulation of CaMKII

Science's STKE  06 Jan 2004:
Vol. 2004, Issue 214, pp. tw5
DOI: 10.1126/stke.2142004tw5

Lu et al. investigated the interaction of calcium/calmodulin-dependent protein kinase II (CaMKII) with Camguk (Cmg), a Drosophila membrane-associated guanylate kinase, and discovered that Cmg participated not only in CaMKII localization but also in regulating its sensitivity to calcium-CaM. CaMKII, which is localized to particular subcellular regions through interactions with various protein partners, has been implicated in the activity-dependent modulation of synaptic efficacy. After determining that CaMKII and Cmg colocalized pre- and postsynaptically and could be reciprocally coimmunoprecipitated, Lu et al. used an in vitro assay to show that adenosine triphosphate (ATP) bound to CaMKII and thereby stimulated its association with Cmg. When the Cmg-CaMKII complex formed in the presence of calcium and CaM, ATP hydrolysis led to CaMKII autophosphorylation at Tyr287. Under these conditions CaMKII was trapped in the complex and constitutively activated. In the absence of calcium and CaM, however, ATP hydrolysis led to CaMKII autophosphorylation at Tyr306, a site in the CaM-binding domain, and dissociation of CaMKII from Cmg. After dissociation from Cmg, CaMKII was inactive and could no longer bind CaM. Cmg suppressed CaMKII activity when cotransfected into a human kidney cell line and, in Drosophila, manipulation of Cmg and protein phosphatase 2 (PP2) expression modulated the postsynaptic phosphorylation of CaMKII at Tyr306 (with Cmg promoting and PP2 reducing Tyr306 phosphorylation). Tyr306 phosphorylation at the neuromuscular junction was inversely related to synaptic activity. These data suggest that Cmg participates in the calcium- and activity-dependent regulation of CaMKII and thus in use-dependent changes in synaptic efficacy.

C. S. Lu, J. J. L. Hodge, J. Mehren, X. X. Sun, L. C. Griffith, Regulation of the Ca2+/CaM-responsive pool of CaMKII by scaffold-dependent autophosphorylation. Neuron 40, 1185-1187 (2003). [Online Journal]