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

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

Neuronal Anatomy

• Cell Body/Soma

• Dendrites– Input-spine

• Axon– Output-bouton

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

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 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

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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

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 spineGoldin, et al., 2001