Alpha2delta-mediated control of neuronal signaling

Alpha2delta 介导的神经信号传导控制

• 批准号: 10590759
• 负责人: Eric Schnell
• 金额: $ 33.98万
• 依托单位: OREGON HEALTH & SCIENCE UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2022
• 资助国家: 美国
• 起止时间: 2022-03-15 至 2027-02-28
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10590759
• 关键词: Acceleration; Action Potentials; Acute; Ataxia; Binding; Binding Proteins; Biological Assay; Brain; Buffers; CNR1 gene; Calcium; Calcium Channel; Calcium Signaling; Cell membrane; Cells; Compensation; Complex; Coupled; Coupling; Data; Development; Diffuse; Disease; Disparate; Drug Modulation; Drug Targeting; Electrophysiology (science); Endocannabinoids; Epilepsy; Family; Fiber; Genes; Hippocampus; Homeostasis; Human; Individual; Inhibitory Synapse; Knockout Mice; Link; Mediating; Mediator; Membrane; Migraine; Molecular; Mus; Mutant Strains Mice; Mutation; Neurologic; Neurons; Pharmaceutical Preparations; Phenotype; Play; Potassium Channel; Presynaptic Terminals; Process; Property; Protein Family; Protein Isoforms; Protein Subunits; Proteins; Publishing; Purkinje Cells; Role; Runaway; Signal Transduction; Slice; Source; Surface; Synapses; Synaptic plasticity; Testing; Virus; Whole-Cell Recordings; autism spectrum disorder; cell type; deafness; endocannabinoid signaling; experimental study; gabapentin; improved; insight; loss of function; mind control; mutant; nano; nervous system disorder; neuronal excitability; neuropathology; neurotransmission; novel; postsynaptic; postsynaptic neurons; presynaptic; prevent; protein function; receptor; synaptic function; trafficking; vesicular release; voltage; voltage clamp

PROJECT SUMMARY Intracellular calcium drives neuronal signaling and excitability, and appropriate spatial and temporal control of neuronal calcium signals are required to prevent dysregulated control of brain activity, which can lead to epileptic seizures. One of the primary sources of calcium in neurons is entry via voltage-gated calcium channels on the cell membrane, which is then coupled to various effector mechanisms through co-localization of channels and calcium-responsive proteins within the neuron. Two specific, but distinct, calcium-dependent processes critical for maintaining brain homeostasis involve retrograde endocannabinoid signaling and the action potential afterhyperpolarization. Endocannabinoids are produced postsynaptically by neurons in a calcium-dependent manner, and then diffuse to presynaptic terminals where they bind to CB1 receptors and powerfully inhibit vesicle release at numerous synapses. Separately, voltage-dependent calcium entry activates nearby coupled calcium-dependent potassium channels, mediating the action-potential afterhyperpolarization which accelerates cell repolarization and controls neuronal firing rates. For each of these phenomena, tight functional coupling of calcium entry to these disparate effectors is critical in maintaining brain function. While the specific cellular mechanisms responsible for controlling the appropriate localization of voltage-gated calcium channels remain largely unknown, our preliminary data indicate a critical role for the alpha2delta proteins in the functional coupling of calcium entry to effectors. These auxiliary calcium channel subunits help traffic voltage-gated calcium channels to the neuronal surface membrane, but have otherwise remained enigmatic despite clear association with neurologic diseases in humans and mice. We hypothesize that the alpha2delta proteins are critical mediators of functional coupling between calcium entry and calcium- dependent signaling throughout the brain. We propose to use genetically modified mice and electrophysiological assays to define the roles of alpha2delta isoforms in 1) calcium-dependent retrograde signaling from cerebellar Purkinje cells to their various synaptic inputs, 2) the control of excitability and endocannabinoid signaling in the hippocampus, and 3) the molecular mechanisms underlying these phenomena using molecular replacement strategies. Together, these experiments will lead to a greatly enhanced appreciation of the function of this important class of calcium channel subunits, which we believe can be leveraged to improve our ability to control runaway excitability in the brain in conditions such as epileptic seizures.

项目总结