Discuss the role of CaMKII (calcium/calmodulin-dependent kinase II) autophosphorylation in learning and memory

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Discuss the role of CaMKII (calcium/calmodulin-dependent kinase II) autophosphorylation in learning and memory.

In my essay, I will be discussing the mechanism of CaMKII autophosphorylation and how this process brings about LTP, which contributes to learning and memory. Furthermore I will talk about how the autophosphorylated kinase interacts with the postsynaptic receptors, which underlies the mechanisms of neuronal plasticity. Neural tissues contain many protein kinases and phosphatases and of these protein kinases, calcium-calmodulin dependent protein kinase II (CaMKII) plays an important role in learning and memory. CaMKII is a Ca2+-activated enzyme and makes up 1-2% of the total protein. The kinase is abundantly found in synapses and is one of the main proteins of the postsynaptic density in the vertebrate central nervous system.

In mammals, there are more than 30 isoforms of CaMKII consisting of 4 genes, which are α,β,γ and δ and have molecular weights ranging from 52-83kDa. The main isoforms in the brain are α and β(Colbran et al, 2004). The α-isoform is found in plentiful amounts in the forebrain whereas the β-isoform is more commonly found in cerebellum (Fink et al, 2002).

These subunits combine together in the brain through subunit association domains to produce dodecameric holoenzymes. Each isoform contains a N-catalytic domain, an autoinhibitory domain, a variable segment and a C-terminal self-association domain. The catalytic domain consists of sites that the ATP and substrate can bind to and also sites that anchoring proteins can interact with. Within the autoinhibitory domain there exists a region that is similar to the protein substrates and this pseudosubstrate region interacts with the substrate-binding site (S site) located in the catalytic domain. In the absence of Ca2+  /calmodulin complex, the autoinhibitory domain interacts with the catalytic domain stopping access to substrate and therefore suppresses enzyme activity. It is said that the autoinhibitory domain acts as a ‘gate’.

When Ca2+/calmodulin interacts with a region that overlaps with the pseudosubstrate region, the gate is opened causing stimulation of the subunit and Threonine 286 is exposed on the autoinhibitory domain. When T286 is exposed, this region is phosphorylated by a surrounding subunit. When this region is phosphorylated, the gate remains open even when Ca2+ levels decline and the Ca2+/calmodulin complex dissociates from the enzyme (Yang et al, 1999). This permits CaMKII to sustain its maximal catalytic activity at lower levels of calcium and in the absence of Ca2+ /CaM,     the enzyme demonstrates limited activity and therefore the kinase functions as a molecular memory enzyme. Thus this CaMKII is an autonomous enzyme, which demonstrates Ca2+ independent activity. T286 is only autophosphorylated by α-CaMKII and β-CaMKII only autophosphorylates T287.

The process by which T286 phosphorylation that makes the enzyme autonomous has recently been established. At both the S and T sites, the gate interacts with the catalytic domain. The area around the unphosphorylated T286 interacts with the T site and this positions the pseudosubstrate sequence, so that the S-site is suppressed.

Phosphorylated T286 cannot bind to the T site and therefore the autoinhibitory domain cannot suppress the S site and the kinase is active (Yang et al, 1999). At the C-terminal end of the kinase, the association domain permits the assembly of a non-dissociable holoenzyme of 12 subunits (Lisman et al, 2002). A variable region that promotes structural differences between isoforms links the catalytic and regulatory domains.

As the concentration of cytosolic calcium increases, calcium binds to calmodulin to form calcium-calmodulin complex. This complex binds to the Ca2+/CaM-binding domain and the autoinhibitory domain no longer binds to the catalytic domain leaving the catalytic domain to phosphorylate substrate molecules (Rongo et al, 2002).When two adjacent subunits in the holoenzyme interact with Ca2+/CaM, T286 will be exposed on the subunit and the adjacent subunit will expose and stimulate its catalytic domain, so that it can phosphorylate the adjacent T286.The autoinhibitory domain will not bind and suppress the catalytic domain due to this intersubunit autophosphorylation even in the absence of Ca2+/CaM. Therefore the autophosphorylated enzyme is active and is Ca2+/CaM independent. The binding of 2 Ca2+/CaM molecules at the same time to 2 adjacent subunits is needed for autophosphorylation. In the presence of low frequency oscillations , the length of time that Ca2+/CaM is present for is not sufficient for 2 Ca2+/Cam molecules to bind to the two adjacent subunits. But with high frequency oscillations, 2 Ca2+/CaM molecules will successfully bind to the subunits and cause autophosphorylation resulting in one active subunit (Rongo et al, 2002). If 1 subunit is active and Ca2+  /CaM independent, coincident binding is no longer required for adjacent subunits to be phosphorylated. So an active subunit will immediately phosphorylate a newly bound adjacent subunit producing 2 active subunits in a holoenzyme. The autophosphorylation of CaMKIIα on T286 is needed for learning in its early stages but is not important for long term storage of the acquired information (Hell et al, 2005).CaMKII is needed for the induction of long-term potentiation (LTP) in the hippocampus and LTP is a widely known cellular mechanism for promoting learning and memory. Normally the activity in the presynaptic neuron does not induce postsynaptic firing where these neurons are connected by synapses and hence there is low efficacy of communication between the neurons. LTP is the mechanism whereby a presynaptic neuron repeatedly induces postsynaptic neuronal firing and hence increases synaptic efficacy (Rongo et al, 2002). The process of LTP occurs in the three main interconnected synaptic circuits of the hippocampus: the perforant pathway from the entorhinal cortex to dentate gyrus, the mossy fiber pathway from dentate gyrus to the CA3 pyramidal cells and the schaffer collateral pathway from CA3 to the CA1 pyramidal cells.

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Figure 1: The 3 pathways in the hippocampus where LTP is observed which are the scaffer collateral pathway, the mossy fiber pathway and the perforant pathway (Rongo et al, 2002).

NMDA receptor subunits contain 3 membrane spanning regions and a C-terminal tail of various lengths, which produces the intracellular portion of the receptor (Strack et al, 1998). NMDA receptors are heteromeric complexes consisting of NR1, NR2 subunits and less commonly NR3 subunits. NR2B can combine with NR1 to form a heteromeric channel or with NR2A and NR1 and this NR2B is shown to be vital for ...

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