Transcript 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
Receptor activation
• 2-5 ligands per
channel
• Ion selectivity
• Inactivation
Neurotransmitters
Transmitter
Inotropic
receptor
Acetylcholine
Excitatory
(nicotinic)
Na/K channel
Glutamate
Serotonin
Glycine
Excitatory
Na/Ca/K
NMDA/AMPA
Excitatory
Na/K
Structure
Transmitter
Metabotropic
receptor
Acetylcholine
Muscarinic
receptor
Glutamate
Metabotropic
glutamate
Serotonin
Serotonin
receptor
GABA
b-type GABA
Dopamine
Dopamine
receptor
Norepinepherine
Adrenergic
receptor
Inhibitory Cl-
GABA
Inhibitory Clg-Aminobutyric
acid
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-methyl4isoxazolepropionic 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
• 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
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
Neuronal Anatomy
• Cell Body/Soma
• Dendrites
– Input-spine
• Axon
– Output-bouton
Dendrite Morphology
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•
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•
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
Spike histogram
– NT reuptake/metabolism
Voltage at “silent” endplate
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+
r
r
Spatial summation
• Transmission loss
Gulledge, et al 2005
Temporal summation
• Facilitation of EPSP by previous EPSP
– Depolarization from depolarized state
– Modification of channel.
• Potentiation
Soma signal processing
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 stimulation
Low Calcium
I1 activates PP1
Decreases AMPA
High frequency stimulation
High Calcium
I1 is inhibited
Reduces PP1
Increases AMPA
Inhibitory modulation
• Synaptic fatigue
– NT depletion
• Presynaptic inhibition
– Reduces AP initiated current & Ca2+ influx
– Metabotropic block of Ca channels
– Activation of Clchannels
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
Flex
Extend
Ventral Flexion Neuron
Dorsal Swim Interneuron
Ventral Swim Interneuron
Stimulate sensory neurons to elicit escape
Intracellular potential
of neurons
Dorsal Flexion Neuron
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
Recording
Stimulation
Blocks metabotropic
process
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