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Ligand gated ion channels Channel structure –Heteropentamer –4-transmembrane pass subunits Neurotransmitter diversity Post synaptic potentials –Excitatory.

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Presentation on theme: "Ligand gated ion channels Channel structure –Heteropentamer –4-transmembrane pass subunits Neurotransmitter diversity Post synaptic potentials –Excitatory."— Presentation transcript:

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 TransmitterInotropic receptor Structure AcetylcholineExcitatory (nicotinic) Na/K channel GlutamateExcitatory Na/Ca/K NMDA/AMPA SerotoninExcitatory Na/K GlycineInhibitory Cl- GABA  -Aminobutyric acid Inhibitory Cl- TransmitterMetabotropic receptor AcetylcholineMuscarinic receptor GlutamateMetabotropic glutamate SerotoninSerotonin receptor GABAb-type GABA DopamineDopamine receptor NorepinepherineAdrenergic receptor

5 Acetylcholine, serotonin receptors Ach, Nicotinic AChR –K+/Na+ permeable –~30 pS  17e6 Na + /s @ 90mV –Broadly distributed, including striated muscle 5-HT 3, 5-hydroxytryptamine –Na+/K+ –Esp raphne nuclei Attention/cognitive function Depression (SSRIs)

6 Glutamate receptors NMDA (N-methyl-D-aspartate) –Na+/K+/Ca2+ –Mg 2+ 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 GABA A receptor  -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 Voltage at “silent” endplate Spike histogram

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 Na V channels –Origin of AP

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

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 Mg 2+ block –Calcium induced channel phosphorylation increases conductance –Long term potentiation Ca2+ influx via NMDA receptors Ca 2+ ->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 & Ca 2+ 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 BurstRest

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

25 Tritonia Metabotropic Neuromodulation DSI stimulation triggers fast and slow depolarization –Slow depolarization is GTP dependent –Blocked by non-hydrolysable GDP-  -S Stimulation Recording Slow metabotropic depolarization Fast Ionotropic 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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