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Principal Investigator: JOSHUA M KAPLAN
Organization: MASSACHUSETTS GENERAL HOSPITAL
Fiscal Year: 2024
Award: $568,605
Funding agency: National Institute of Neurological Disorders and Stroke
Analysis of calcium signaling in C. elegans
The goal of this project is to analyze mechanisms controlling signaling by
voltage-activated calcium (CaV) channels. In neurons and muscles, brief cytoplasmic
calcium transients efficiently and rapidly activate downstream effectors, often on
millisecond time scales. One general mechanism that promotes signal speed and
efficiency is tight spatial coupling between CaV channels and their effectors, which is
termed calcium nanodomain signaling. We propose three Aims to study nanodomain
signaling by CaV channels. First, we identify genes required to promote coupling of
CaV1 (L-type) channels to two effectors, calcium activated BK potassium channels and
ryanodine receptors (RYR), which are calcium release channels in the endoplasmic
reticulum. Second, we test models for how the threshold is set for activity induced gene
transcription, and if this threshold is shifted by mutations in specific calcium activated
signaling components or by endogenous neuropeptides. Third, we ask how CaV1 and 2
channels are localized at presynaptic terminals, which dictates neurotransmitter release
probability. These Aims address fundamental mechanisms controlling neuron and
muscle physiology.
Terms: <ATP-protein phosphotransferase><Action Potentials><Address><Autoregulation><Axon Terminals><BK channels><Basal Transcription Factor><Basal transcription factor genes><Big K channels><Binding Proteins><Biology><Biophysics><C elegans><C. elegans><C.elegans><CREB><CREB1><CREB1 gene><Ca Release Channel-Ryanodine Receptor><Caenorhabditis elegans><Calcineurin><Calcium><Calcium Channel><Calcium Channel Antagonist Receptor><Calcium Channel Blocker Receptors><Calcium Ion Channels><Calcium Ion Signaling><Calcium Signaling><Calcium-Dependent Activator Protein><Calcium-Dependent Regulator><Calcium-Ryanodine Receptor Complex><Calmodulin><Candidate Disease Gene><Candidate Gene><Cell Body><Cell Communication and Signaling><Cell Signaling><Cells><Coupled><Coupling><Cytoplasm><Defect><Endoplasmic Reticulum><Enzyme Gene><Enzymes><Ergastoplasm><Frequencies><Gene Transcription><General Transcription Factor Gene><General Transcription Factors><Genes><Genetic><Genetic Alteration><Genetic Change><Genetic Transcription><Genetic defect><Goals><HDAC><HDAC Proteins><HDAC4><HDAC4 gene><HDACA><Histone Deacetylase><Histone Deacetylase 4><Histone Deacetylase A><Homeostasis><Intracellular Communication and Signaling><K channel><Kinase Family Gene><Kinases><Ligand Binding Protein><Ligand Binding Protein Gene><MaxiK channels><Mediating><Membrane><Modeling><Molecular><Motor Cell><Motor Neurons><Msec><Muscle><Muscle Cell Contraction><Muscle Contraction><Muscle Tissue><Muscle function><Muscular Contraction><Mutation><Myoneural Junction><Nerve Cells><Nerve Transmitter Substances><Nerve Unit><Nervous System Diseases><Nervous System Disorder><Neural Cell><Neurocyte><Neurologic Disorders><Neurological Disorders><Neuromuscular Junction><Neurons><Neuropeptides><Neurotransmitters><PP2B><Pathologic><Pattern><Phosphodiesterase Activating Factor><Phosphodiesterase Protein Activator><Phosphoprotein Phosphatase><Phosphoprotein Phosphatase-2C><Phosphoprotein Phosphohydrolase><Phosphotransferase Gene><Phosphotransferases><Physiological Homeostasis><Play><Potassium Channel><Potassium Ion Channels><Presynaptic Nerve Endings><Presynaptic Terminals><Probability><Protein Binding><Protein Kinase><Protein Phosphatase C><Protein Phosphatase Gene><Protein Phosphatase-1><Protein Phosphatase-2A><Protein Phosphatase-2B><Protein phosphatase><RNA Expression><Receptor Activation><Role><Ryanodine Receptor><Ryanodine Receptor Calcium Release Channel><Signal Transduction><Signal Transduction Systems><Signaling><Source><Speed><Synapses><Synaptic><Synaptic Boutons><Synaptic Receptors><Synaptic Terminals><Testing><Time><Transcription><Transcription Factor Proto-Oncogene><Transcription factor genes><Transphosphorylases><VDCC><Voltage-Dependent Calcium Channels><biological signal transduction><biophysical foundation><biophysical principles><biophysical sciences><bound protein><cAMP Response Element-Binding Protein 1><cell type><experiment><experimental research><experimental study><experiments><genome mutation><glycogen synthase a kinase><hydroxyalkyl protein kinase><insight><large-conductance calcium-activated potassium channels><maxi-K channels><membrane structure><millisecond><motoneuron><muscle physiology><muscular><mutant><mutation scanning><mutation screening><nano><nanometer><neurological disease><neuronal><neurotransmitter release><optogenetics><phosphorylase b kinase kinase><postsynaptic><receptor coupling><recruit><response><slowpoke protein><social role><synapse><synapse function><synaptic function><transcription factor><voltage>