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CaMKII
Posted Date: 19 May 2008 Resource Type: Articles/Knowledge Sharing Category: General
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Posted By: sharu Member Level: Gold
Rating:  Points: 1
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Brain is the site of reason and intelligence, which includes such components as cognition, perception, attention, learning, memory and emotion. Learning is the acquisition and development of memories and behaviors, including skills, knowledge, understanding values and wisdom while memory is an organism's ability to store, retain and subsequently retrieve information. Physiologically, memories are caused by changes in the capacity of synapses to transmit activity from one neuron to another in a neural circuit as a result of previous neural activity. These changes in turn cause new pathways to develop in the neural circuitry. The new pathways are called memory traces. They are important because once established, they can be activated by the thinking process to reproduce memories whenever required.
There are many key regulatory molecules involved in memory acquisition, consolidation, and retrieval. The two most important molecules in this category are:
• CaMKII
• NMDAR
Originally identified as an abundant brain protein found at the postsynaptic density. CaMKII is regulated by calcium through its interaction with calmodulin. Cells typically maintain intracellular calcium level of 10-7 M, 104 times lower than the level outside. Thus extracellular calcium may enter the cell through voltage-gated calcuim channels and ligand-gated receptors or can be released from intracellular sources. The predominant intracellular receptor for calcium is calmodulin.
Many of the cellular responses to calcium signals are induced or modulated by a family of multifunctional Ca2+ /Calmodulin-dependent protein kinases. CaMKII is an important member of calcium/calmodulin-activated protein kinase familiy in neural synaptic stimulation and T-cell receptor signalling.
CaMKII is an oligomeric Ser/Thr protein kinase. Multiple isoforms of human CaMKII are encoded by four genes (a, ß, ? and d) that are spliced differentially to produce more than 20 isoforms of the enzyme. Thus the kinase is comprised of multiple subunits that associate to form a holoenzyme. Each subunit is comprised of a bilobed catalytic domain (which includes an amino- terminal lobe containing the catalytic core and a carboxy- terminal lobe containing multiple alpha helices), an autoinhibitory domain and an association domain. In the absence of calcium signalling, CaMKII is inactive because the autoinhibitory domain binds to the catalytic domain along two hydrophobic pockets, thereby preventing access to substrate. In the presence of calcium signalling, calcium- bound calmodulin binds to specific residues within the autoinhibitory domain, causing its displacement and exposing a critical threonine, T286, on the autoinhibitory domain. The T286 residue is phosphorylated by adjacent subunits in the holoenzyme upon displacement by Ca/CaM. Once phosphorylated at T286, the autoinhibitory domain can no longer interact with the catalytic domain, thus allowing the catalytic domain to access and phosphorylate substrates.
CaMKII is described as a cognitive kinase because of its involvement in regulating forms of learning and memory and its autoregulatory properties that can be viewed as a molecular memory. It phosphorylates proteins that modulate presynaptic transmission, as well as a host of receptors and signaling molecules in the postsynaptic cell, a process that is widely accepted as critical for synaptic plasticity. Different frequencies of synaptic activation lead to alterations in the strength of neurotransmission that may last for hours to days, referred to as long-term potentiation (LTP) or long-term depression.
Many important features of CaMKII are the direct consequences of its multimeric structure and autoregulation; including its capacity to undergo autophosphorylation that (a) reduces its Ca2+/CaM dependence following dissociation of CaM, (b) increases its affinity for Ca2+/CaM by more than 1000-fold, and (c) enables it to function as a Ca2+ spike frequency detector.
Finally, autophosphorylation of Thr286 exposes a site on the enzyme that allows its binding to an anchoring protein, the N-methyl-D-aspartate (NMDA)-subtype of glutamate receptor.
Threonine to aspartate (T286D) substitutions can mimic autophosphorylation of CaMKII by intoducing a negative charge on the autoinhibitory domain resulting in the displacement of the domain and calcium independent activity. The generation of this autonomous kinase may underlie some long term enhancement of transient calcium signals.
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