ligand gated ion channels channel structure –heteropentamer –4-transmembrane pass subunits...
TRANSCRIPT
Ligand gated ion channels
• Channel structure– Heteropentamer– 4-transmembrane pass subunits
• Neurotransmitter diversity
• Post synaptic potentials– Excitatory– Inhibitory
• Modulation
Neurotransmitters
Transmitter Inotropic receptor
Structure
Acetylcholine Excitatory (nicotinic) Na/K channel
Glutamate Excitatory Na/Ca/K
NMDA/AMPA
Serotonin Excitatory Na/K
Glycine Inhibitory Cl-
GABA
-Aminobutyric acid
Inhibitory Cl-
Transmitter Metabotropic receptor
Acetylcholine Muscarinic receptor
Glutamate Metabotropic glutamate
Serotonin Serotonin receptor
GABA b-type GABA
Dopamine Dopamine receptor
Norepinepherine Adrenergic receptor
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)
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
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
GABAA 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
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
Dendrite Morphology
• Multiple synapses
• Multiple morphologies
• Synaptic plasticity
• EPSP/IPSP
VI Popov et al., 2004 Neuroscience
Endplate potential
• Miniature endplate potentials– Release of a single NT quantum– Quantal size– Receptor efficacy– NT reuptake/metabolism
Voltage at “silent” endplate
Spike histogram
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
Spatial summation
• Depolarization due to single channel
• Multple synchronous channels
Na+Na+
r
Na+Na+
r
Na+Na+
r
Temporal summation
• Facilitation of EPSP by previous EPSP– Depolarization from depolarized state– Modification of channel.
• Potentiation
Signal modulation
• Potentiation
• Pre-synaptic inhibition
• Plateau potentials
• Metabotropic interaction
• Synaptic remodeling
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 stimulationLow CalciumI1 activates PP1Decreases AMPA
High frequency stimulationHigh CalciumI1 is inhibitedReduces PP1
Increases AMPA
Inhibitory modulation
• Synaptic fatigue– NT depletion
• Presynaptic inhibition– Reduces AP initiated current & Ca2+ influx– Metabotropic block of Ca channels– Activation of Cl-
channels
Plateau potentials
• Neuronal bistability– Bursting triggered by brief depolarization– Terminated by brief hyperpolarization
• Mechanism– T-Type calcium channels– Sodium current
Burst Rest
Metabotropic neurotransmission
• G-protein coupled receptors– No direct ionic current– Activation of secondary signaling cascade
Sea slug (tritonia) locomotion
• Characteristic escape response
• Alternate, vigorous body flexion
• Simple neural circuit
Lawrence & Watson 2002
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
ExtendIn
tracellular p
oten
tialo
f neu
ron
s
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