Saturday, June 27, 2009

CaMK (Ca2+/calmodulin-dependent protein kinase)


Ca2+/calmodulin-dependent protein kinase (CaMK) are a family of Ser/Thr protein kinases whose activity is regulated by Ca2+/calmodulin (CaM) complex and on activation, phosphorylate their protein substrates to alter their functionality1. They are primarily located in the brain and play a critical role in neuronal development, plasticity and behavior1.


In 1979, the idea that CaMK exists arose from the observation that most of the Ca2+-dependent endogenous phosphorylation of rat brain cytosol proteins require calmodulin2. Later, in 1980, CaMKII was purified from rat brain by gel filtration techniques while monitoring the activation of tryptophan hydrolase and phosphorylation of endogenous proteins3.


CaMK proteins belong to the kinase family4. CaMK subfamily of proteins includes the following members: CaMKI, CaMKII-alpha subunit, CaMKII-beta subunit, CaMKII-gamma subunit, CaMKII-delta subunit, CaMKIII and CaMKIV4.

Structural Characteristics

The CaM kinases consist of an N-terminal catalytic domain followed by autoinhibitory and Ca2+/CaM binding domains. In addition CaMKII proteins have an association domain5. The enzymes assemble into dodecameric holoenzyme structures, with the catalytic domains sticking out, such that these may phosphorylate residues in an intersubunit fashion that increases their affinity to CaM complex6. In the absence of Ca2+/calmodulin, the autoinhibitory domain inhibits the catalytic domain6. Several CaM kinases aggregate into a homooligomer or heterooligomer. Phosphorylation at residues 286/305/306, which are all threonines, have a negative effect on binding of Ca2+/calmodulin complex to enzyme subunits, thus reducing function6.

Mode of action

When intracellular Ca2+ increases, CaM binds up to four Ca2+ ions to form the Ca2+/CaM complex that binds to the regulatory domain of CaMK thereby activating the enzyme with half maximal activation at Ca2+. After this Ca2+/CaM-dependent activation, CaMK autophosphorylates Thr287 on the autoinhibitory segment resulting in a completely active enzyme that can maintain CaMK active even after Ca2+ has declined7. Activated CaMKs can phosphorylate various substrates7.


CaMK proteins play an important role in the development of neurons8. CaMKK/CaMKI is involved in regulation of axonal growth cone morphology/motility and axonal outgrowth, dendritic arborization, and formation of dendritic spines8. CaMKII modulates excitation contraction coupling in the heart by regulating several Ca2+ handling proteins8. CaMKII has also been implicated in Ca2+ dependent axonal growth cone attraction, synaptic plasticity, learning and memory1. CaMKIV promotes dendritic growth by the activationof ErK1.


1. Wayman GA, Lee YS, Tokumitsu H, Silva A, Soderling TR (2008). Calmodulin-kinases: modulators of neuronal development and plasticity. Neuron, 59(6), 914-31.

2. Yamauchi T and Fujisawa H (1980). Evidence for three distinct forms of calmodulin-dependent protein kinases from rat brain. FEBS Lett., 116, 141-144.

3. Yamauchi T, Fujisawa H (1979). Most of the Ca2+-dependent endogenous phosphorylation of rat brain cytosol proteins requires Ca2+-dependent regulation protein. Biochem Biophys Res Commun., 90(4), 1172-8.

4. Steven KH and Tony H (1995). The eukaryotic protein kinase superfamily: kinase (catalytic) domam structure and classification. The Faseb Journal, 29, 576-96.

5. Thomas RS and James TS (2001). Structure and Regulation of Calcium/Calmodulin-Dependent Protein Kinase. Chem. Rev., 101 (8), 2341–52.

6. Rosenberg OS, Deindl S, Sung RJ, Nairn AC, Kuriyan J (2005). Structure of the autoinhibited kinase domain of CaMKII and SAXS analysis of the holoenzyme. Cell, 123, 849–860.

7. Lars SM and Donald MB (2007). Role of Ca2+/calmodulin-dependent protein kinase (CaMK) in excitation–contraction coupling in the heart. Cardiovascular Research, 73(4), 631-640.

8. Alicia M, Leticia V and Cecilia MW (2007). Ca2+/calmodulin-dependent protein kinase: A key component in the contractile recovery from acidosis. Cardiovascular Research, 73(4), 648-656.

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