Neurotransmitter-gated Ion Channels

A brief overview
Reading: 1. Malmivuo & Plonsey, BEM - web edition: Ch. 5.

http://www.bem.fi/book/index.htm

Emilia Entcheva, SUNY Stony Brook, BME301, Spring 2012

Ligand-gated Ion Channels

Emilia Entcheva, SUNY Stony Brook, BME301, Spring 2012

Goals
1. How are ligand-gated ion channels different? 2. Synapse structure 3. Functional features of the synapse 4. Varieties of neurotransmitter-sensitive channels 5. Disease example
Emilia Entcheva, SUNY Stony Brook, BME301, Spring 2012

Reflex Arc. Sensors and Actuators

afferent
Information processing unit (spinal cord / brain)

efferent

sensors

actuators

knee jerk reflex 1 synapse

Emilia Entcheva, SUNY Stony Brook, BME301, Spring 2012

Synapses
1. Essential in transmission of information in the nervous system Variety: neuro-neuro (NN); neuro-myo (NM). Single neuron 1000 synaptic endings; single spinal motor neuron 10,000 synaptic inputs. No electrical signal transmission from pre- to postsynaptic cell Chemical transmission (switch) triggers electrical signal in the post-synaptic cell
Emilia Entcheva, SUNY Stony Brook, BME301, Spring 2012

2.

3.

4.

Synaptic Cleft (15-30nm)

1. Release of neurotransmitter (exocytosis of vesicles in the synaptic cleft) 2. Binding of neurotransmitter to receptor 3. Depolarization or hyper-polarization of post-synaptic axon

Emilia Entcheva, SUNY Stony Brook, BME301, Spring 2012

N-M

N-N

Emilia Entcheva, SUNY Stony Brook, BME301, Spring 2012

Neuromuscular Junction
Neuromuscular junction (NMJ) also known as motor end plate

End plate potential is transmembrane potential of muscle fiber

Emilia Entcheva, SUNY Stony Brook, BME301, Spring 2012

Neurotransmitters
1. 2. Present in pre-synaptic neuron Released upon stimulation in pre-packaged vesicles via exocytosis

3.

Micro-application on post-synaptic neuron should mimic effect of stimulation of pre-synaptic

Pharmacologic agents affect both micro-application and stimulation similarly

4.

Emilia Entcheva, SUNY Stony Brook, BME301, Spring 2012

Neurotransmitters
Acetylcholine
Glutamate -aminobutyric acid (GABA) Epinephrine and norepinephrine, dopamine, serotonin (5-hydroxytryptamine), glycine Peptides such as histamine
Emilia Entcheva, SUNY Stony Brook, BME301, Spring 2012

Neurotransmitter Receptors
Each neurotransmitter may bind to more than one kind of receptor
A receptor may bind more than one kind of neurotransmitter Binding of neurotransmitter to receptor can lead to direct changes of an associated ion channel, or affect ion channels indirectly through other second messenger systems
Emilia Entcheva, SUNY Stony Brook, BME301, Spring 2012

IPSPs and EPSPs

The depolarization of the postsynaptic membrane in response to a neurotransmitter is termed excitatory post synaptic potential (EPSP)
The hyperpolarization of the postsynaptic membrane in response to a neurotransmitter is termed inhibitory post synaptic potential (IPSP)
Emilia Entcheva, SUNY Stony Brook, BME301, Spring 2012

Equivalent circuit (ligand = switch)

Emilia Entcheva, SUNY Stony Brook, BME301, Spring 2012

Temporal Summation
If more neurotransmitter is released before the already existing neurotransmitters are cleared, then the concentration of neurotransmitters will increase The release has to occur fast enough to increase the concentration of neurotransmitters and hence increase concentration of activated ion channels

Emilia Entcheva, SUNY Stony Brook, BME301, Spring 2012

Spatial Summation
If more than one presynaptic axon synapses with the postsynaptic dendrite, then firing of more than one axon increases the local neurotransmitter concentration

Emilia Entcheva, SUNY Stony Brook, BME301, Spring 2012

Integrative Role of Synapses

Through both temporal and spatial summation, plus the possibility of two different actions of neurotransmitters (IPSP and EPSP), there is a wide variability of outcomes (consider binary vs. analog)
1012 neurons, 1015 synapses in the human brain neural net

Forms the basis for complexity of the nervous system

Emilia Entcheva, SUNY Stony Brook, BME301, Spring 2012

Acetylcholine
Nicotinic acetylcholine receptor (nAChR)
1. ACh binds to AChR 2. AChR undergoes conformational change permitting influx of cations (mostly Na+) 3. Ach is removed and AChR returns to its original shape

Emilia Entcheva, SUNY Stony Brook, BME301, Spring 2012

Effects of ACh binding to AChR

Influx of cations, principally Na+, result in depolarization (EPSP) Membrane voltage pulled toward ENa by increased conductance for Na

g Na gCl gK Em EK ENa ECl gT gT gT gT g K g Na gCl

Emilia Entcheva, SUNY Stony Brook, BME301, Spring 2012

Glutamate
Excitatory amino acid receptors (EAAR) bind glutamate and other amino acids:
AMPA: Na+ and K+ NMDA: Na+, K+, and Ca2+

Induces depolarization
Emilia Entcheva, SUNY Stony Brook, BME301, Spring 2012

GABA and Glycine

Receptors structurally resemble AChR However, permits passage only of anions GABA and glycine receptors mediate flow of Cl- ions, i.e. ligand-gated chloride channels

GABA and glycine are considered inhibitory neurotransmitters because they lead to IPSP by virtue of their permitting influx of Clleading to hyperpolarization

Emilia Entcheva, SUNY Stony Brook, BME301, Spring 2012

Parkinsons disease (PD) is a dopamine deficiency disorder.

The Case of Parkinsons Disease

Dopamine is a neurotransmitter, released by neurons in the midbrain; plays an important role in motor control and psychological processes and perceptions.

Tyrosine (Tyrosine hydroxylase)-> L-Dopa (Dopa Decarboxylase)-> Dopamine In PD, dopamine-producing neurons die out PD primary symptoms include motor-control impairments: trembling in the limbs and face; stiffness of the limbs; slowness of movements and difficulty walking; impaired balance.

Secondary PD symptoms include depression, speech difficulty, dementia, sexual problems.

Secondary symptoms due to disturbed balance of dopamine/acetylcholine
Emilia Entcheva, SUNY Stony Brook, BME301, Spring 2012

The Case of Parkinsons Disease

Brainstorm treatment solutions

Emilia Entcheva, SUNY Stony Brook, BME301, Spring 2012