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Ligand gated ion channels

Ligand gated ion channels. Channel structure Heteropentamer 4-transmembrane pass subunits Neurotransmitter diversity Post synaptic potentials Excitatory Inhibitory Modulation. Structure. Pentameric Charged pore Cation/anion selective 4-pass monomer Cytoplasmic basket.

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Ligand gated ion channels

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  1. Ligand gated ion channels • Channel structure • Heteropentamer • 4-transmembrane pass subunits • Neurotransmitter diversity • Post synaptic potentials • Excitatory • Inhibitory • Modulation

  2. Structure • Pentameric • Charged pore • Cation/anion selective • 4-pass monomer • Cytoplasmic basket

  3. Receptor activation • 2-5 ligands per channel • Ion selectivity • Inactivation

  4. Neurotransmitters

  5. Acetylcholine, serotonin receptors • Ach, Nicotinic AChR • K+/Na+ permeable • ~30 pS  17e6 Na+/s @ 90mV • Broadly distributed, including striated muscle • 5-HT3, 5-hydroxytryptamine • Na+/K+ • Esp raphne nuclei • Attention/cognitive function • Depression (SSRIs)

  6. Glutamate receptors • NMDA (N-methyl-D-aspartate) • Na+/K+/Ca2+ • Mg2+ dependent voltage gating • AMPA (amino-3—hydroxy-5-methyl-4isoxazolepropionic acid) Quisqualate • Modest, 12 pS conductance • Some are Ca2+ permeable; excitotoxicity • Kainate • Low, 4 pS conductance

  7. Inhibitory neurotransmitters • Structurally similar to excitatory • 5 subunit • Dual-ligand binding • Chloride conductance • Adult: inhibitory • Developmental: excitatory • Higher intracellular Cl- • K+/Cl- co-transporter • Upregulated late in development • Exports Cl- to establish ~-120mV equilibrium potential

  8. GABAA receptor • g-Aminobutyric Acid • Cl- channel, 18 pS, 20 ms • Major inhibitory receptor in CNS • Anesthetic target (barbiturates) • Channel agonists • Increase conductivity • Addiction • Reduced expression of calmodulin kinase

  9. Glycine receptor • Relatively little receptor diversity • 4 alpha subunits, 1 beta • Strychnine binding • 90 pS • Retina, spinal motor, spinal pain • Phosphorylation reduces conductivity • Zinc • nM-uM zinc potentiates • >10 uM Zn2+ inhibits

  10. Neuronal Anatomy • Cell Body/Soma • Dendrites • Input-spine • Axon • Output-bouton

  11. Dendrite Morphology • Multiple synapses • Multiple morphologies • Synaptic plasticity • EPSP/IPSP VI Popov et al., 2004 Neuroscience

  12. Endplate potential • Miniature endplate potentials • Release of a single NT quantum • Quantal size • Receptor efficacy • NT reuptake/metabolism Spike histogram Voltage at “silent” endplate

  13. Endplate potential • Actual NT release causes EPSP/IPSP • Single synapse • Extremely regular • Sub-threshold • Spatial summation • Multiple inputs • High resistance dendrites • No AP means no amplification • Axon hillock • High density NaV channels • Origin of AP

  14. Na+ Na+ Na+ Na+ Na+ Na+ r r r Spatial summation • Depolarization due to single channel • Multple synchronous channels

  15. Spatial summation • Transmission loss Gulledge, et al 2005

  16. Temporal summation • Facilitation of EPSP by previous EPSP • Depolarization from depolarized state • Modification of channel. • Potentiation

  17. Soma signal processing

  18. Signal modulation • Potentiation • Pre-synaptic inhibition • Plateau potentials • Metabotropic interaction • Synaptic remodeling

  19. NMDA receptor mediated plasticity • Glutamineric synapses have both AMPA and NMDA receptors • Long term potentiation: Tetanus increases subsequent EPSPs • Tetanic depolarization relieves Mg2+ block • Calcium induced channel phosphorylation increases conductance • Long term potentiation • Ca2+ influx via NMDA receptors • Ca2+->PKA-|I1->PP1-|AMPA Low frequency stimulation Low Calcium I1 activates PP1 Decreases AMPA High frequency stimulation High Calcium I1 is inhibited Reduces PP1 Increases AMPA

  20. Inhibitory modulation • Synaptic fatigue • NT depletion • Presynaptic inhibition • Reduces AP initiated current & Ca2+ influx • Metabotropic block of Ca channels • Activation of Cl-channels

  21. Plateau potentials • Neuronal bistability • Bursting triggered by brief depolarization • Terminated by brief hyperpolarization • Mechanism • T-Type calcium channels • Sodium current Burst Rest

  22. Metabotropic neurotransmission • G-protein coupled receptors • No direct ionic current • Activation of secondary signaling cascade

  23. Sea slug (tritonia) locomotion • Characteristic escape response • Alternate, vigorous body flexion • Simple neural circuit Lawrence & Watson 2002

  24. Flex Extend Dorsal Flexion Neuron Ventral Flexion Neuron Dorsal Swim Interneuron Ventral Swim Interneuron Tritonia CPG • Escape is a programmed response • Katz, et al., 2004 Intracellular potential of neurons Stimulate sensory neurons to elicit escape

  25. Recording Stimulation Tritonia Metabotropic Neuromodulation • DSI stimulation triggers fast and slow depolarization • Slow depolarization is GTP dependent • Blocked by non-hydrolysable GDP-b-S Fast Ionotropic depolarization Slow metabotropic depolarization Blocks metabotropic process

  26. Synaptic remodeling • Rearrangement of neural networks • Hebbian elimination • Vision • Synchronous signals are strengthened • Remodeling of dendritic spines • Calcium dependent cell motility Stimulation of cultured neuron results in rapid development of a new dendritic spine Goldin, et al., 2001

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