Synonym |
CAMK2A |
Species |
Human |
Protein Accession |
P11277 |
Purity |
≥95% |
Endotoxin Level |
<1.0 EU per μg protein |
Biological Activity |
Not specified |
Expression System |
Insect Cells |
Fusion Tag |
His Tag |
Predicted Molecular Mass |
53.2 kDa |
Formulation |
Liquid in 25 mM Tris-HCl buffer |
Reconstitution |
No reconstitution needed. Simply thaw and use. |
Storage & Stability |
Store at -80°C. For long term storage, store at -80°C or -20°C. |
FAQ
How does (Ala286)-Calmodulin-Dependent Protein Kinase II contribute to cellular signal transduction, and
why is it significant?
(Ala286)-Calmodulin-Dependent Protein Kinase II, specifically
characterizes a modified version of the enzyme that plays a pivotal role in cellular signal
transduction. Calmodulin-Dependent Protein Kinase II (CaMKII) is a multifunctional enzyme, essential in
translating calcium signals, which are ubiquitous in many cellular processes. Calcium ions act as a
universal signaling molecule, responding to various external stimuli and modulating numerous
intracellular pathways. CaMKII becomes activated upon binding to the calcium/calmodulin complex, which
is indicative of elevated intracellular calcium levels.
The significance of CaMKII, and
particularly its variant (Ala286), lies in its ability to phosphorylate a multitude of substrates within
the cell, influencing numerous physiological processes. The Ala286 mutation influences the enzyme's
autophosphorylation capability, which is critical for sustaining its activity even after the calcium
signal diminishes. This feature is particularly crucial in the context of neuronal functions where it
impacts synaptic plasticity – a fundamental mechanism underlying learning and memory. When activated,
CaMKII can phosphorylate synaptic proteins, leading to modifications in their structure and function,
thus affecting the strength and efficacy of synapses. Such synaptic alterations are essential for
processes like Long-Term Potentiation (LTP), which is a long-lasting increase in synaptic strength
following high-frequency stimulation.
Research into (Ala286)-CaMKII continues to unravel its
contributions to neuronal plasticity and its potential role in neurodegenerative diseases. Moreover,
given that dysregulation of calcium-dependent signaling pathways is implicated in a variety of
pathological conditions, understanding the specific roles and regulatory mechanisms of CaMKII can
illuminate pathways for therapeutic interventions. Beyond the nervous system, CaMKII is involved in
other vital processes including cardiac function, where it influences heart muscle contraction and
rhythmicity by modulating ion channel activity. Its ubiquitous presence across different tissues
underscores the enzyme’s broad biological significance, making it a crucial element in the study of
cellular signaling dynamics and a potential target for modulating responses in diseases characterized by
aberrant calcium signaling.
What research developments have there been recently concerning
(Ala286)-Calmodulin-Dependent Protein Kinase II?
Recently, advancements in the study of
(Ala286)-Calmodulin-Dependent Protein Kinase II have expanded significantly, primarily driven by the
integration of cutting-edge techniques in structural biology, genomics, and neurosciences. Studies have
increasingly focused on elucidating the structural intricacies of the Ala286 mutation to gain deeper
insights into the functional enhancements attributed to this form of CaMKII. Using cryo-electron
microscopy and X-ray crystallography, researchers have been able to visualize the three-dimensional
conformational changes in (Ala286)-CaMKII, delineating the specific mechanistic pathways it engages in
upon autophosphorylation. This structural insight is essential as it informs the biochemical basis of
its prolonged activity, even in the absence of calcium/calmodulin binding.
Moreover, genomic
studies have leveraged CRISPR-Cas9 technology to create mutant strains and cell lines that express the
Ala286 variant of CaMKII to observe the resultant physiological and behavioral changes. These models
have been instrumental in exploring the role of (Ala286)-CaMKII in memory retention and cognitive
flexibility in animal models, thereby enhancing our understanding of its impact on learning processes.
Additionally, these genetic models have helped delineate how aberrations in this kinase might contribute
to neurodegenerative conditions and cognitive disorders, offering potential therapeutic
targets.
In neuroscience, the application of optogenetics and advanced in vivo imaging techniques
has revealed how (Ala286)-CaMKII modulates synaptic activity and neuronal circuits in real-time. Such
studies have highlighted its essential role in synapsis-specific plasticity and how it orchestrates
complex behaviors through the modulation of synaptic strength over time. Furthermore, in the context of
cardiac research, there has been a concerted effort to study the role of (Ala286)-CaMKII in cardiac
hypertrophy and heart failure, aiming to differentiate its beneficial and maladaptive roles in heart
tissue remodeling and calcium handling.
Collectively, these research developments underline the
broadened scope of knowledge regarding (Ala286)-CaMKII and establish a foundation for future exploration
into therapeutic approaches that can harness its activity to treat conditions marked by calcium
dysregulation. The interplay of different methodologies and collaborative research networks has thus
significantly propelled the understanding of this nuanced kinase and its role within broader
physiological contexts.
What are the challenges associated with targeting
(Ala286)-Calmodulin-Dependent Protein Kinase II in therapeutic treatments?
Targeting
(Ala286)-Calmodulin-Dependent Protein Kinase II in therapeutic treatments presents several challenges,
stemming from the complexity of its biological roles and the delicate balance of its signaling
activities. One of the primary challenges lies in achieving specificity in targeting (Ala286)-CaMKII
without adversely affecting other isoforms of CaMKII that perform distinct and essential functions in
various tissues. The kinase's ubiquitous expression across different organ systems implies that any
therapeutic intervention must precisely discern its beneficial functions from its pathogenic
roles.
Another challenge is related to the autophosphorylation activity of (Ala286)-CaMKII, which
can perpetuate its activity even in the absence of calcium, making it difficult to regulate once
activated. This persistent activity necessitates designing therapeutic agents that can either
selectively inhibit the hyperactive state of the kinase or promote its dephosphorylation, restoring
normal regulatory control without disrupting regular cellular calcium signaling, which is vital for
numerous physiological processes.
The structural conformations of (Ala286)-CaMKII add another
layer of complexity, as interventions that affect its structure could lead to unforeseen consequences on
its interaction with a wide array of substrates and binding partners. Additionally, the transient and
localized nature of calcium-dependent signaling that involves CaMKII complicates the ability to target
its activity with precision, maintaining local signaling specificity while avoiding systemic side
effects.
Furthermore, consideration must be given to the compensatory pathways that might be
activated when (Ala286)-CaMKII is inhibited. Inhibition could potentially lead to upregulation or
downregulation of other kinases and pathways, altering cellular homeostasis and triggering undesired
side effects. This necessitates a comprehensive understanding of the kinase's role in cellular networks
to anticipate and mitigate any compensatory mechanisms that might compromise therapeutic
efficacy.
Clinical translation of research targeting (Ala286)-CaMKII also faces hurdles in the
form of delivery systems. Developing drug delivery methods that ensure adequate bioavailability,
penetrance, and retention in target tissues without eliciting off-target actions presents an additional
challenge. Moreover, inter-individual variability in genetic make-up and disease pathology requires
personalized approaches to ensure that therapeutic targeting of (Ala286)-CaMKII is both safe and
effective across different patient populations.
In summary, while the therapeutic targeting of
(Ala286)-CaMKII offers potential benefits in conditions characterized by aberrant calcium signaling, it
is fraught with challenges that necessitate carefully designed strategies to harness its mechanisms
without disrupting critical cellular functions. Continued research into its regulation, structural
dynamics, and involvement in broader signaling pathways is essential to overcome these
challenges.
How does (Ala286)-Calmodulin-Dependent Protein Kinase II influence learning and
memory processes?
(Ala286)-Calmodulin-Dependent Protein Kinase II (CaMKII) plays an influential
role in learning and memory processes through its critical involvement in synaptic plasticity, which is
the cellular mechanism underlying these cognitive functions. Synaptic plasticity refers to the ability
of synapses, the communication junctions between neurons, to strengthen or weaken over time in response
to increases or decreases in activity. CaMKII, particularly in its (Ala286) variant, is essential for
initiating and maintaining these modifications, thereby facilitating the encoding and storage of
information in neural circuits.
The activation of (Ala286)-CaMKII is triggered by the binding of
calcium-bound calmodulin, which occurs when there is an influx of calcium ions into the neuron following
synaptic activation. Upon activation, (Ala286)-CaMKII undergoes autophosphorylation, a self-modification
that substantially prolongs its active state, allowing it to sustain activity even in the absence of
continuous calcium signals. This prolonged activity plays a pivotal role in the induction and
maintenance of long-term potentiation (LTP), a persistent strengthening of synapses that is widely
recognized as a foundational mechanism for memory formation and learning.
(Ala286)-CaMKII
influences learning and memory by modifying the properties of synaptic receptors. For instance, one of
its key functions is the regulation of AMPA-type glutamate receptors at the synapse, which determines
the synaptic response to glutamate, a major excitatory neurotransmitter in the brain. By phosphorylating
these receptors, (Ala286)-CaMKII enhances their conductance, thereby increasing synaptic strength and
facilitating the LTP process.
Moreover, (Ala286)-CaMKII's ability to bind to specific sites
within the synaptic architecture allows it to scaffold additional signaling molecules, orchestrating a
multi-layered signaling complex that crucially influences the structural components of the postsynaptic
density. This role is instrumental in initiating structural changes that support synaptic scaling and
remodeling, critical aspects of learning and memory.
Additionally, (Ala286)-CaMKII serves as a
molecular memory switch. Its autophosphorylation confers the ability to retain a 'memory' of past
calcium signals, enabling neurons to adapt to new inputs based on previous experiences. This property
underscores its status not only as a signaling molecule but also as a molecular integrator of past and
present signals, thus playing a strategic role in both the short-term and long-term memory
consolidation.
Further research delves into the specific contributions of (Ala286)-CaMKII in the
pathophysiology of memory-related disorders, highlighting its potential as a therapeutic target to
ameliorate cognitive impairments. Its central role in synaptic plasticity and the dynamic regulation of
neural connectivity makes it an invaluable focus of study in the quest to understand and harness the
cognitive capabilities of the human brain.
What are the physiological roles of
(Ala286)-Calmodulin-Dependent Protein Kinase II beyond the nervous system?
Beyond its
well-documented role in the nervous system, (Ala286)-Calmodulin-Dependent Protein Kinase II (CaMKII)
performs a myriad of physiological functions across different body systems, underlining its versatility
as a key regulatory enzyme. Its widespread presence and functional implications showcase the kinase's
involvement in various cellular processes and biological contexts outside the neuronal
milieu.
One of the primary roles of (Ala286)-CaMKII beyond the nervous system is in the
cardiovascular field. It is instrumental in regulating heart muscle contraction and cardiac rhythm
through its action on calcium channels and other cardiac proteins. Specifically, it modulates the
activity of sarcoplasmic reticulum calcium release channels, which are critical for the
excitation-contraction coupling in cardiac myocytes. By influencing calcium cycling within these cells,
(Ala286)-CaMKII plays a significant role in both cardiac contractility and arrhythmogenesis. This dual
role makes it a critical factor in the physiological adaptation of heart muscle to various stressors and
pathological conditions such as heart failure and hypertrophy.
In skeletal muscle,
(Ala286)-CaMKII contributes to the regulation of muscle contraction and metabolism by modulating calcium
signaling pathways involved in muscle fiber adaptation to exercise. It affects mitochondrial biogenesis
and influences aerobic metabolism, thereby contributing to overall muscular endurance and performance.
Additionally, it has a role in the regulation of glucose uptake in response to insulin, implicating it
in energy homeostasis and metabolic health.
In the immune system, (Ala286)-CaMKII facilitates the
activation and differentiation processes of lymphocytes. It participates in the signaling cascades
triggered by antigen receptor engagement on immune cells, thereby aiding in adaptive immune responses.
Its involvement in these pathways exemplifies its function in the immune surveillance mechanisms and
response regulation, making it relevant in the context of immune disorders and
inflammation.
Furthermore, (Ala286)-CaMKII is involved in the regulation of gene expression
through transcriptional modulation in several cell types. By participating in the regulation of
signaling pathways that control nuclear factor activity, (Ala286)-CaMKII contributes to gene expression
patterns that determine cellular responses to therapeutic agents and environmental stressors,
influencing processes such as cell growth, differentiation, and apoptosis.
In conclusion, the
roles of (Ala286)-CaMKII extend well beyond neuronal signal transduction, impacting various functional
aspects in cardiovascular physiology, muscle metabolism, immune function, and gene regulation. Its
multifunctional nature and systemic relevance continue to be a central focus of research, holding
promise for therapeutic insights not only in neurobiology but in broader biomedical contexts where
calcium-dependent signaling is pivotal.