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Ligand-Gated Ion Channels: The Big Picture

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Chian Wright
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42 views

Ligand-Gated Ion Channels: The Big Picture

Uploaded by

Chian Wright
Copyright
© © All Rights Reserved
We take content rights seriously. If you suspect this is your content, claim it here.
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Download as PPT, PDF, TXT or read online on Scribd
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Action potentials travel

Ligand-gated ion down the axon leading to


neurotransmitter release.
channels: the big
picture

This is chemical
neurotransmission.
Drugs acting at LGICs

 Thiopental (induction anesthetic) – GABAA-R

 Ondansetron (anti-emetic) - 5HT3-R

 Succinylcholine (muscle relaxant) – nAChR

 Ketamine (veterinary anesthetic) – NMDA-R

 Diazepam, clonazepam, etc. (sedative/anxiolytic) – GABAA-R

 Perampanel (anti-epileptic) – AMPA-R

 Memantine (Alzheimer’s drug) – NMDA-R

 Strychnine (poison) - GlyR

 Ethanol, inhaled anesthetics – GABAA-R, GlyR, NMDA-R, ??


Neurotransmitters are small molecules released by
neurons that bind to receptors and elicit functional effects.

Glutamate
GABA

Dopamine Serotonin Acetylcholine


What happens after neurotransmitters
bind to receptors?

Excitatory postsynaptic potentials (EPSPs)


increase the likelihood of action potential
generation in the postsynaptic cell (increases
membrane potential- makes it more positive).

Inhibitory PSPs (IPSPs) decrease the


likelihood of action potential generation (may
decrease membrane potential).
Nature of postsynaptic cell’s response to
neurotransmitter depends on:
 
 the type of neurotransmitter released
 the type of receptor(s) on the postsynaptic cell 
 the magnitude of the response to neurotransmitter
which itself depends on:
 quantity of neurotransmitter released
 receptor numbers
 state of the receptors
Two major categories of neurotransmitter receptors 

 Ionotropic – Neurotransmitter binding causes a


conformational change in the receptor which leads
to the rapid opening of the pore in the receptor,
permitting ions to flow down their electrochemical
gradients.  
 Metabotropic – Neurotransmitter binding causes a
conformational change in the receptor which leads
to a second messenger cascades (ie through G-
protein activation). These responses are of slow
onset and long duration, compared to ionotropic
receptors.  We’ll cover these in the next lecture.
General characteristics of ionotropic
receptors

 Multi-subunit protein complexes with


membrane-spanning domains
 Very fast onset (submillisecond time
scale)
 Ion selectivity (eg. cation vs. anion
selectivity)
 Most desensitize rapidly after
exposure to agonist
Major Types of Ionotropic (Ligand-gated ion) channels
Glutamate Receptors (NMDA and Non-NMDA) Cys-loop Ion Channels
(GABAA, Gly, nACh and 5-HT3 Receptors)

1
In the nAChR three rings of negatively charged
amino acids face the pore. These ensure that only
cations can pass through the pore.

5
4 1
3 2

1 2 3 4 5
Ions interact
with specific
amino acids of
pores and are
dehydrated
during pore
passage.
Acetylcholine binding to the receptor
There are two binding sites for acetylcholine in the extracellular
domain of the receptor, and cooperativity of binding between
the two sites is evident.
If you only have a few kinds of transmitters,
how do you maintain diversity?
GABA Glycine
 - 6 subunits   - 4 subunits
  - 4 subunits   - 1 subunit
  - 4 subunits
  - 1 subunit
  - 1 subunit Amino acid sequence homology is
  - 1 subunit greatest within classes (eg. 1 vs.
6) of subunits (~70% homology)
  - 1 subunit
compared to between ( vs. 
  - 3 subunits
classes (~30-40% homology).

The subunit compositions of recombinant receptors


determine their pharmacological profiles.
Consequences of agonist binding to a
neurotransmitter receptor


k+1 

k-1
Use of the patch clamp technique
to measure single channel function
The opening and
closing events exhibited
by individual ion
channels result in the
averaged currents seen
by electrophysiologists
not performing single
channel
measurements.

Average open time is


on the ~1 ms timescale.
GABAAR and GlyR are the major
inhibitory neurotransmitters in the
brain and spinal cord (conduct Cl-
ions).

Inhibition of GABAA or Gly receptors cause convulsions


(picrotoxin). Enhancement of GABAA or Gly receptor function
would be expected to lead to sedation and anaesthesia
(think alcohol and volatile anaesthetics).
Clinically useful
allosteric modulators
zinc
have effects on
receptor function.
An example of an allosteric modulator:
Benzodiazepines

 eg., diazepam (Valium®), flunitrazepam (Rohypnol®), chlordiazepoxide


(Librium®)
 Clinically useful as sedatives, hypnotics, anxiolytics, anticonvulsants.
Danger of tolerance and dependence.
 Agonists at the benzodiazepine receptor site enhance GABA-mediated
currents by left-shifting the GABA concentration-response curve.
 Benzodiazepines have no effects in the absence of GABA.

GABA + benzo

GABA
alone

GABA Concentration

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