Revisão proteina CaMKII

Ca2+/calmodulin-dependent protein kinases II or CaM kinases II are serine/threonine-specific protein kinases that are regulated by the Ca2+/calmodulin complex. CaMKII is involved in many signaling cascades and is thought to be an important mediator of learning and memory.[1]CaMKII is also necessary for Ca++ homeostasis and reuptake in cardiomyocytes[2] chloride transport in epithelia,[3] positive T-cell selection,[4] and CD8 T-cell activation.[5] Misregulation of CaMKII is linked to Alzheimer’s

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  Ca 2+  /calmodulin-dependent protein kinases II or  CaM kinases II are serine/threonine-specific protein kinases that are regulated by the Ca 2+ /calmodulin complex. CaMKII is involved in many signaling cascades and is thought to be an important mediator of learning and memory. [1] CaMKII is also necessary for Ca++ homeostasis and reuptake incardiomyocytes [2]  chloride transport in epithelia, [3]  positive T-cell selection, [4] and CD8 T-cell activation. [5] Misregulation of CaMKII is linked to Alzheimer’s disease, Angelman’s syndrome, and heart arrhythmia. [6] Types There are two types of CaM kinase  Specialized CaM kinases . An example is the myosin light chain kinase (MLCK) that phosphorylatesmyosin,  causing smooth musclesto contract.  Multifunctional CaM kinases . Also collectively called CaM kinase II  , which play a role in many processes, suchasneurotransmitter secretion, transcription factor  regulation, andglycogen metabolism. The structure of the association domain of CaMKII gamma rendered by pymol from PDB 2ux0 (left) space fill holoenzyme (center) cartoonholoemzyme (right) cartoon monomeThe structure of the kinase domain of CaMKII rendered by pymol from PDB 2v70, green sticks = nucleotide [edit] Structure, Function, and Autoregulation   Activation and Autoregulation of CaMKII Calcium/calmodulin-dependent protein kinase II (CaMKII) is an enzyme that accounts for 1-2% of all of the proteins in thebrain. Thiskinase can exist as 28 differentisoforms.The isoforms of CaMKII derive from the alpha, beta, gamma, and delta genes.[edit] Structural Domains of CaMKII  All of the isoforms of CaMKII have certain core structural components. CaMKII’s structural domains include: a catalyticdomain, autoinhibitory domain, variable segment, and self-association domain. [7] The catalytic domain of CaMKII has several binding sites for ATP and other substrate anchor proteins. It governs theenzyme’s phosphorylation and is shaped in the form of two hexameric rings. The autoinhibitory domain features apseudosubstrate site. The pseudosubstrate site binds to the protein’s catalytic domain, thus blocking its ability tophosphorylate proteins. [8] The structural feature that governs this autoinhibition is the Threonine 286 residue.Phosphorylationof this site willpermanently activate the CaMKII enzyme. Once the Threonine 286 residue has been phosphorylated, the inhibitorydomain is blocked from the pseudosubstrate site. This effectively blocks autoinhibition, allowing for permanent activation of the CaMKII enzyme. This enables CamKII to be active, even in the absence of calcium and calmodulin. [9] The other two domains in CaMKII are the variable and self-association domains. Differences in these domains contributeto the various CaMKII isoforms. [10] The self-association domain (CaMKII AD) is found at theC terminus, the function of this domain is the assembly of thesingle proteins into large (8 to 14 subunits) multimers  [11] [edit] Calcium and Calmodulin Dependence of CaMKII The sensitivity of the CaMKII enzyme to calcium and calmodulin is governed by the variable and self-associative domains.This sensitivity level of CaMKII will also modulate the different states of activation for the enzyme. Initially, the enzyme isactivated; however, autophosphorylation does not occur because there is not enough Calcium or calmodulin present tobind to neighboring subunits. As greater amounts of calcium and calmodulin accumulate, autophosphorylation occursleading to persistent activation of the CaMKII enzyme for a short period of time. However, the Threonine 286 residueeventually becomes dephosphorylated, leading to inactivation of CaMKII. [12] [edit]  Autophosphorylation  Autophosphorylation is the process in which a kinase attaches a phosphate group to itself. When CaMKII isautophosphorylated, it becomes persistently active. Phosphorylation of the Threonine 286 site allows for the activation of the catalytic domain. Autophosphorylation is enhanced by the structure of the holoenzyme because it is present in twostacked rings. The close proximity of these adjacent rings increases the probability of phosphorylation of neighboringCaMKII enzymes, furthering autophosphorylation. [13] A mechanism that promotes autophosphorylation features inhibition of the PP1 phosphatase. This enables CaMKII to be constantly active by increasing the likelihood of autophosphorylation. [14] [edit] Long-Term Potentiation Calcium/ calmodulin dependent protein kinase II is also heavily implicated in long-term potentiation(LTP) – the molecular  process of strengthening active synapses that is thought to underlie the processes of memory. It is involved in manyaspects of this process. LTP is initiated when theNMDA receptors(which act as “molecular coincidence receptors” andallow this process to be the result of BOTH pre- and post-synaptic neuron activation) allow Ca2+ into the post synapticneuron. This Ca2+ influx activates CaMKII. It has been shown that there is an increase in CaMKII activity directly in thepost synaptic density of dendrites after LTP induction, suggesting that activation is a direct result of stimulation. [15]   [16] [edit] CaMKII is necessary for LTP When alpha-CaMKII is knocked out in mice, LTP is reduced by 50%. This can be explained by the fact that beta-CaMKII isresponsible for approximately 65% of CaMKII activity. [17]   [18] LTP can be completely blocked if CaMKII is modified so that itcannot remain active. [2]   [19]   After LTP induction, CaMKII moves to the postsynaptic density (PSD). However if the stimulation  does not induce LTP, the translocation is quickly reversible. Binding to the PSD changes CaMKII so that it is less likely tobecome dephosphorylated. CaMKII transforms from a substrate for Protein Phosphatase 2A (PP2A), which is responsiblefor dephosphorylating CaMKII, to that of Protein Phosphatase 1. Strack, S. (1997) [15]   demonstrated this phenomenon bychemically stimulating hippocampal slices. This experiment illustrates that CaMKII contributes to the enhancement of synaptic strength. Sanhueza et al. [20] found that persistent activation of CaMKII is necessarily for the maintenance of LTP.He induced LTP in hippocampal slices and experimentally applied an antagonist (CaMKIINtide) to prevent CaMKII fromremaining active. The slices that were applied with CaMKIINtide showed a decrease in Normalized EPSP slope after thedrug infusion, meaning that the induced LTP reversed itself. The Normalized EPSP slope remained constant in the control;CaMKII continues to be involved in the LTP maintenance process even after LTP establishment. CaMKII is activated bycalcium/calmodulin, but it is maintained by autophosphorylation. CaMKII is activated by the NMDA-receptor-mediatedCalcium elevation that occurs during LTP induction. Activation is accompanied by phosphorylation of both the alpha andbeta-subunits and Thr286/287.[edit] CaMKII can independently induce LTP LTP can be induced by artificially injecting CaMKII. When CaMKII is infused in postsynaptically in the hippocampal slicesand intracellular perfusion or viral expression, there is a two- to threefold increase in the response of the synapse toglutamate and other chemical signals. [21]   [22] [edit] Mechanistic role in LTP There is strong evidence that after activation of CaMKII, CaMKII plays a role in the trafficking of   AMPA receptors into the membrane and then the PSD of the dendrite. Movement of AMPA receptors increases postsynaptic response topresynaptic depolarization through strengthening the synapses. This produces LTP.Mechanistically, CaMKII phosphorylates AMPA receptors at the P2 serine 831 site. This increases channel conductance of GluA1 subunits of AMPA receptors, [23] which allows AMPA receptors to be more sensitive than normal during LTP.Increased AMPA receptor sensitivity leads to increase synaptic strength.In addition to increasing the channel conductance of GluA1 subunits, CaMKII has also been shown to aid in the process of  AMPA receptor exocytosis. Reserve AMPA receptors are embedded in endosomes within the cell. CaMKII can stimulatethe endosomes to move to the outer membrane and activate the embedded AMPA receptors. [24] Exocytosis of endosomesenlarges and increases the number of AMPA receptors in the synpase. The greater number of AMPA receptors increasesthe sensitivity of the synapse to presynaptic depolarization, and generates LTP.[edit] Maintenance of LTP  Along with helping to establish LTP, CaMKII has been shown to be crucial in maintaining LTP. Its ability toautophosphorylate is thought to play an important role in this maintenance. Administration of certain CaMKII blockers hasbeen shown not only to block LTP but also to reverse it in a time dependent manner . [25] [edit] CaMKII in Behavioral Memory  As LTP is thought to underlie the processes of learning and memory, CaMKII is also crucial to memory formation.Behavioral studies involving genetically engineered mice have demonstrated the importance of CaMKII.[edit] Preventing Autophosphorylation of CaMKII [edit] Deficit in Spatial Learning In 1998, Giese and colleagues studied knockout mice that have been genetically engineered to prevent CaMKIIautophosphorylation. They observed that mice had trouble finding the hidden platform in the Morris water maze task. TheMorris water maze task is often used to represent hippocampus-dependent spatial learning. The mice’s inability to find thehidden platform implies deficits in spatial learning. [14] However, these results were not entirely conclusive because memory formation deficit could also be associated withsensory motor impairment resulting from genetic alteration. [26] [edit] Deficit in Fear Memories Irvine and colleagues in 2006 showed that preventing autophosphorylation of CaMKII cause mice to haveimpaired initial  learning of fear conditioning. However, after repeated trials, the impaired mice exhibited similar fear memory formation as the control mice. CaMKII may play a role in rapid fear memory, but does not completely prevent fear memory in the long run. [27] In 2004, Rodrigues and colleagues found that fear conditioning increased phosphorylated CaMKII in lateral amygdalasynapses and dendritic spines, indicating that fear conditioning could be responsible for regulating and activating the  kinase. They also discovered a drug, KN-62, that inhibited CaMKII and prevented acquisition of fear conditioning and LTP. [28] [edit] Deficit in Consolidation of Memory Traces α-CaMKII heterozygous mice express half the normal protein level as the wild-type level. These mice showed normalmemory storage in the hippocampus, but deficits in consolidation of memory in the cortex. [29] [edit] Overexpressing CaMKII Mayford and colleagues engineered transgenic mice that express CaMKII with a point mutation of Thr-286 to aspartate,which mimics autophosphorylation and increases kinase activity. These mice failed to show LTP response to weak stimuli,and failed to perform hippocampus-dependent spatial learning that depended on visual or olfactory cues. [30] Researchers speculate these results could be due to lack of stable hippocampal place cells in these animals. [31] However, because genetic modifications might cause unintentional developmental changes,viral vector delivery allows themice’s genetic material to be modified at specific stages of development. It is possible with viral vector delivery to inject aspecific gene of choice into a particular region of the brain in an already developed animal. Poulsen and colleagues in2007 used this method to inject CaMKII into the hippocampus. They found that overexpression of CaMKII resulted in slightenhancement of acquisition of new memories. [32] [edit] Different forms of CaMKII [edit] CaMK2A CaMKIIA is one of the major forms of CamKII. It has been found to play a critical role in sustaining activation of CamKII atthe postsynaptic density. Studies have found that knockout mice without CaMKIIA demonstrate a low frequency of LTP. Additionally, these mice do not form persistent, stable place cells in the hippocampus. [33] [edit] CaMK2B CaMK2B has an autophosphorylation site at Thr287. It functions as a targeting or docking module. Reverse transcription-polymerase chain reaction and sequencing analysis identified at least five alternative splicing variants of beta CaMKII(beta, beta6, betae, beta'e, and beta7) in brain and two of them (beta6 and beta7) were first detected in any species. [34] [edit] CaMK2D CaMK2D appears in both neuronal and non-neuronal cell types. It is characterized particularly in many tumor cells, suchas a variety of pancreatic, leukemic, breast and other tumor cells. [35] found that CaMK2D is downregulated in human tumor cells.[edit] CaMK2G CaMK2G has been shown to be a crucial extracellular signal-regulated kinase in differentiated smooth muscle cells. [36] [edit] CaMKII Coding Genes  CaMK I — CAMK1, CAMK1D, CAMK1G  CaMK II —CAMK2A, CAMK2B, CAMK2D, CAMK2G  CaMK IV —CAMK4[edit] References 1. ^ Yamauchi, Takashi (2005). Neuronal Ca2+/Calmodulin-Dependent Protein Kinase II—Discovery,Progress in a Quarter of a Century, and Perspective: Implication for Learning and Memory . Biological &Pharmaceutical Bulletin   28 (8): 1342–54. doi:10.1248/bpb.28.1342.PMID 16079472. 2. ^  a   b   Anderson, M (2005). Calmodulin kinase signaling in heart: an intriguing candidate target for therapy of myocardial dysfunction and arrhythmias . Pharmacology & Therapeutics   106 : 39–55.doi:10.1016/j.pharmthera.2004.11.002.
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