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In neurons calcium acts as a secondary messenger and it regulates mitochondrial respiration, neurotransmitter synthesis, development, gene transcription, glycogenolysis and more related function to this study learning and memory via signal transduction (Berridge et al., 1998).
Calcium enters to the cell via voltage gated channel and receptor operated pathways. It also enters via Ryanodine receptors and endoplasmic reticulum (Berridge, 1993; Berridge et al., 1998).
As stated above calcium acts as a second messenger that is essential for neurotransmitter synthesis, memory and learning. The process responsible for this function is called Ca2+ induced Ca2+ release (CICR). The process is vital in the pre-synaptic terminal and imperatively the post-synaptic terminal where generation of Ca2+ waves occurs to amplify Ca2+ influx (Verkhratsky, 2002).
Glutamate is an excitatory neurotransmitter which is notably Ca2+ dependent because of its dependence on Ca2+ mediated proteins (Melamed et al., 1993).
Î±CaMKII is an example of Ca2+ mediated protein which phosphorylates synapsin I. Menegon, 2002 suggested that the Synapsin I is responsible to prevent translocations of synaptic vesicles to the pre-synaptic membrane by binding to synaptic vesicle in the central and peripheral nervous system (Koizumi et al., 1999; Menegon, 2002).
Small excitatory response of glutamate due to inward flow of sodium can activate AMPA receptors. (Î±-amino-3-hydroxyl-5-methyl-4-isoxazole-propionate). However same level of excitatory response from glutamate is unable to activate NMDA receptor (N-methyl-D-aspartic acid), which is calcium and sodium permeable, due to Mg2+ outside the cell. However if there is a strong depolarization effect from glutamate this can results in NMDA receptor activation by disassociating Mg2+. Upon the receptor activation the target cell can react with dissimilar synaptic stimulation (Bading et al.1995). Long Term Potentiation (LTP) is the result of this activation which contributes to memory and learning. LTP enhances synaptic transmission which improves the ability of comminication between pre-synaptic and post-synaptic neurons (Otmakhova et al., 2000).
Figure 000: show NMDA receptor upon activation where Ca2+ influx occures
When NMDA receptor is activated (Figure 000) it results in Ca2+ influx into the cell and which activates Î±CaMKII and initiates translocation of the enzyme near the NMDA receptors identified as post synaptic density (PSD). During this process autophosphorylation of the enzyme occurs which is has been proposed that Î±CaMKII undergo autonomous activity, effectively meaning that enzyme remain in its active state activation in the absence of Ca2+/CaM complex (Ghosh & Greenberg, 1995; Bayer et al., 2001).
1.3 -Understanding Ca2+/CaM complex
Calmodulin (CaM) (figure 1.1, 000), from CALcium MODulated protein, is a ubiquitous Ca2+ binding-protein that expressed as a monomer of molecular weight of 17 kd . Calmodulin belongs to the EF-hand homolog family, consisting of C-terminal and N-terminal lobes. Each of these lobes contains two calcium binding sites. When Ca2+ level are increased inside the cell through signaling mechanisms, the free Ca2+ binds to the lobes on the calmodulin. This interaction results in calmodulin to form a Ca2+/Calmodulin complex containing hydrophobic residues which then interact and activate CaMKII  ( Babu 1985; da Silva & Reinach 1991; Gnegy 1993).
CaM is capable of binding to many different enzymes and proteins. Ca2+ enters cell via voltage gated channels and bind the Ca2+ binding sites on CaM forming Ca2+/CaM complex. This complex then binds to Î±CaMKII and results in the enzyme activation and cell signalling (Jurado et al., 1999). Each of N and C terminal lobes hold two calcium binding sites therefore as soon as the calcium level is raised during signaling mechanisms it will cause these regions to bind to calcium ions. Calmodulin has three different conformational states. The first one is called apocalmodulin (figure 111), effectively meaning that CaM with no Ca2+ attached, the second one is when Ca2+/CaM bind has formed upon Ca2+ influx into the cell, and lastly Ca2+/CaM bound to the target protein.
Figure 111: shows apocalmodulin structure. The N-terminal domain, the C-terminal domain, and the flexible linker between the two domains shown in white.
The structure of CaM looks like a dumbbell in where the two globular section are connected to each other by a 26 residue flexible ï¡-helix (Persechini & Kretsinger, 1988; Kuboniwa 1995). The long ï¡-helix of the last helix of the first domain plus the first helix of the second domain are accountable in making different loop sizes so the complex could bind to the different target enzymes and proteins (Meador 1993).
At each globular residue on the calmodulin, there are two EF-hand regions in the N-terminal (I-II) and two EF-hand regions in the C-terminal (III-IV). In contract with the regions in the N-terminal, the regions in the C-terminal have a 10 fold elevated affinity to Ca2+. (Linse 1991).
Figure 1.1: shows schematically demonstrated amino acid sequence of CaM. The calcium binding regions are I, II, III and IV (Klee, 1988).
1.3.1 -Structure of apocalmodulin
Apocalmodulin effectively means calmodulin but in a state that no Ca2+ attached to it. Apocalmodulin has closely packed hydrophobic residues between the Î±-helices which results in forming a hydrophobic core inside the structure (Jurado44Chockalingam, & Jarrett 1999). Figure 1.2 shows the apocalmodulin structure which has four firmly twisted anti-parallel Î±-helices. This structure is the result of arrangement of helices making inter-helix angles of 128o - 137o in each EF-hand regions by helices (Zhang et al., 1995).
Figure 1.2: shows 3D structure of apocalmodulin containing two globular domains, and each domain consisting of two EF-hand regions. Flexible ï¡-helix region has separated the two globular domains. The anti-parallel beta sheets shown in brown flat arrows (Kuboniwa1995).
1.3.2 - Crystal structure of Ca2+/CaM complex
As states earlier on apocalmodulin consist of a hydrophobic core within the original configuration. This structure is kept by two helices in each EF-hand region forming inter-helix angles of 128o - 137o (Jurado, Chockalingam, and Jarrett, 1999). When free calcium binds to CaM it causes Ca2+ induced conformational change. Upon interaction between Ca2+ and the calmodulin the distance between the two EF-hand helix rises which results in the reduction of inter-helix angles to 86 o -101 o (Figure 1.3) giving different loop size so it can bind to the target enzymes (Jurado44 Chockalingam,&Jarrett,1999). The importance of this conformational change in the original structure is formation of the hydrophobic residues on the surface of each domain. These hydrophobic regions are displayed outwards so they can bind to the hydrophobic residues of the ï¡-helix of a target enzyme or protein (Kubinowa, 1995Kretsinger1997).
Figure 1.3: shows 3D structure of Ca2+/CaM complex. The Ca2+/CaM conformation change enables the helices in the EF-hands to roll out and expose the hydrophobic core to the outer surface of the configuration and stretches the central helix. (Babu, Bugg&Cook1985)
1.3.3 - Crystal structure of Ca2+/CaM attached to Î±CaMKII
After Ca2+/CaM complex formation it becomes capable of binding to the different target enzymes and proteins including Î±CaMKII. According to the results from crystallized Ca2+/CaM it was understood that the hydrophobic regions of the calmodulin and the hydrophobic region of the target enzyme interact with each other (Meador1993).
Hanson and Schulman (1992) report about Thr305/306 autophosphorylation that can inhibit Ca2+/CaM binding to Î±CaMKII can be acceptable by observation of the crystal structure (Figure 1.4) (Hanson and Schulman 1992). In addition, the suggestion that Thr286 autophosphorylation is as a result of Ca2+/CaM induced autoinhibitory domain rearrangement can be understood in the crystal structure observation as the enzyme is seven residues short of Thr286 (Colbran2004).
Fig 1.4: shows 3D structure of Ca2+/CaM after binding to ï¡CaMKII290-314 enzyme. CaMKII conformation is condensed due to the central helix separating the two globular domains in the Ca2+/CaM conformation to bend (Meador et al., 1993).