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Principal Investigator: Margaret M Stratton
Organization: UNIVERSITY OF MASSACHUSETTS AMHERST
Fiscal Year: 2022
Award: $312,941
Funding agency: National Institute of General Medical Sciences
PROJECT SUMMARY
How does a memory outlast the lifetime of the molecule that encodes it? More than two decades ago, Francis
Crick had the foresight to speculate that perhaps a multimeric protein could serve as a molecular memory by
sharing its activation state with newly synthesized proteins through subunit exchange in order to store a
memory for years. Ca2+-calmodulin dependent protein kinase II (CaMKII) was identified as an enzyme that may
fit this description. For example, mutation of CaMKII at sites critical for its function results in severe learning
and memory defects. CaMKII is activated at a threshold neuronal spike frequency and is crucial to long-term
potentiation (LTP). A major obstacle to understanding LTP is the absence of understanding how regulatory
pathways recruited during this initial high-frequency stimulus are able to remain persistently active in the face
of ongoing protein turnover. Our recent work has shown that CaMKII exchanges subunits between
holoenzymes in an activation-dependent manner. Importantly, kinase activity is conferred to unactivated
CaMKII holoenzymes by trans-phosphorylation as a consequence of subunit exchange, thereby potentiating
the activation signal past the time of protein degradation. This cycle may continue indefinitely. Our work is
aimed to further investigate this phenomenon, specifically in respect to its role in LTP. Our major research
goals are to: 1) understand the role of the unique biophysical properties of CaMKII (how linker length affects
activation, frequency dependence and subunit exchange) that contribute to its potential for being a `memory
molecule,' and 2) investigate the properties of CaMKII (such as subunit exchange and changes in gene
expression) in cellular systems to determine its physiological role in LTP. These challenging goals require the
synthesis of information obtained from the molecular level (protein structure and regulation) to the cellular level
(mammalian cell culture) and finally to the animal level (transgenic mice), which will be for future study.
Completion of the proposed work will allow us to better address neurologic disease progression as it affects
memory, such as pathologies seen in Alzheimer's, dementia, and traumatic brain injury.
Terms: <AD dementia><Address><Affect><Alzheimer><Alzheimer Type Dementia><Alzheimer disease><Alzheimer sclerosis><Alzheimer syndrome><Alzheimer's><Alzheimer's Disease><Alzheimer's disease dementia><Alzheimers Dementia><Alzheimers disease><Ammon Horn><Animals><Assay><Bioassay><Biochemical><Biochemistry><Biologic Assays><Biological Assay><Biological Chemistry><Biophysics><Biosensor><Brain><Brain Nervous System><Brain Trauma><CaM KII><CaM PK II><CaM kinase II><CaMKII><Cell Body><Cell Communication and Signaling><Cell Culture Techniques><Cell Signaling><Cells><Cellular biology><Cornu Ammonis><Data><Defect><Dendrites><Dependence><Disease Progression><Encephalon><Enzyme Gene><Enzymes><Event><Frequencies><Future><Gene Expression><Genetic Alteration><Genetic Change><Genetic defect><Goals><Hand><Hippocampus><Hippocampus (Brain)><Holoenzymes><In Vitro><Intracellular Communication and Signaling><Isoforms><Kinases><Learning><Length><Long-Term Potentiation><Longterm Potentiation><Maintenance><Mammalian Cell><Measures><Memory><Metabolic Protein Degradation><Modeling><Molecular><Monitor><Mutation><Nerve Cells><Nerve Impulse Transmission><Nerve Transmission><Nerve Unit><Nervous System Diseases><Neural Cell><Neural Transmission><Neurocyte><Neurologic Disorders><Neurological Disorders><Neuronal Transmission><Neurons><Pathology><Pathway interactions><Phosphorylation><Phosphotransferase Gene><Phosphotransferases><Physiologic><Physiologic pulse><Physiological><Play><Position><Positioning Attribute><Primary Senile Degenerative Dementia><Process><Property><Protein Isoforms><Protein Phosphorylation><Protein Turnover><Proteins><Pulse><Regulation><Regulatory Pathway><Regulatory Protein Degradation><Research><Role><Signal Pathway><Signal Transduction><Signal Transduction Systems><Signaling><Site><Stimulus><Synapses><Synaptic><Synaptic Transmission><System><Time><Transgenic Mice><Transphosphorylases><Traumatic Brain Injury><Work><axon signaling><axon-glial signaling><axonal signaling><biological sensor><biological signal transduction><biophysical characteristics><biophysical characterization><biophysical foundation><biophysical measurement><biophysical parameters><biophysical principles><biophysical properties><biophysical sciences><calcium-dependent CaM kinase II><calmodulin-dependent protein kinase II><cell biology><cell culture><cell cultures><dementia of the Alzheimer type><experience><fascinate><genome mutation><glia signaling><glial signaling><hippocampal><improved><in vivo><long term memory><longterm memory><nerve signaling><nervous system disorder><neural signaling><neurological disease><neuronal><neuronal signaling><neurotransmission><novel><pathway><primary degenerative dementia><programs><protein degradation><protein structure><protein structures><proteins structure><recruit><senile dementia of the Alzheimer type><shared memory><social role><synapse><traumatic brain damage>