Ion Selection: Cationic Channels

1
Superfamilies of Ligand-gated Ion Channels

• 1. Cys-loop Receptors
• Nicotinic ACh receptors
• 5HT-3 receptors
• GABAA and GABAC receptors
• Glycine receptors

• 2. Ionotropic Glutamate Receptors
• AMPA-type Receptors
• Kainate-type Receptors
• NMDA-type Receptors

3. ATP (P2X) Receptors
4. TRP Receptors
2
Topologies of ligand-gated channels
Kandel, Schwartz Jessel, Principles of Neural
Science 4th Ed. (2000)
3
Ion Selection Cationic Channels
Gate Region
Acidic Residues
Modified from Keramidas et al., Prog. Biophys.
Mol. Biol. 86 161 (2004)
4
GABA and Glycine receptors

• ?-amino-butyric acid (GABA) is the principle
  inhibitory transmitter in the brain.
• GABA receptors are cis-loop receptors thus, they
  are pentamers of at least four different types of
  subunits.
• 6 ? subunits, 3 ? subunits, 3 ? subunits, ?, ?,
  ?, and ? subunits.
• In general, ?, ?, and ?? subunits are all
  required for receptor function.
• Only a limited number of subunit combinations
  exist.

• Glycine (Gly) is the predominant inhibitory
  transmitter in the spinal cord.
• Glycine receptors are pentamers of two different
  types of subunits.
• 4 ? subunits, and 1 ? subunit
• Stoichiometry is 3?2?

5
GABA Receptor Subunit Composition
GABA receptors usually contain at least one each
of ?, ?, and ? subunits.
A typical subunit composition
Two GABA Binding Sites at a-b Interfaces
Benzodiazepine Site at a-g Interface
Katzung (Ed.) Basic Clinical Pharmacology,
Lange (2004)
6
Ion Selection Chloride Channels
Gate Region
Basic Residues
Modified from Keramidas et al., Prog. Biophys.
Mol. Biol. 86 161 (2004)
7
GABA-R Predicted Interaction Between Cys-Cys
Loop and TM2-TM2 Linker
Kash et al., Nature 421 272 (2003)
8
Gating of GABA Channels InteractionBetween the
Cys-Loop and the M2-M3 Linker
K279 in linker D149 in loop
Kash et al., Nature 421 272 (2003)
9
Pharmacology of Inhibitory Receptors
GABA agonists
Benzodiazipines Valium (diazepam) Ambien
(zolpidem, short acting)
Barbiturates Phenobarbital Secobarbital
(Seconal)
10
Benzodiazepines and Barbiturates EnhanceGABAA
Currents Through Different Mechanisms
Probability of Opening
Open Time
Twyman et al (1989) Ann. Neurol. 25 213-220
(1989)
11
GABA and Glycine Antagonists
GABA antagonists Bicuculline
picrotoxin
Glycine antagonist Strychnine
12
Clustering of Receptors at the Postsynaptic
Membrane
The Neuromuscular Junction
From Banks, Froehner et al. J. Neurocytol. 32,
709 (2003)
13
Clustering of Receptors at the Postsynaptic
Membrane
Glycine and GABA receptors (inhibitory junctions)
From Kneussel and Loebrich, Biol. Cell 99, 297
(2007)
14
Topology of Glutamate Receptors
Kandel, Schwartz Jessel, Principles of Neural
Science 4th Ed. (2000)
15
Ionotropic Glutamate Receptor Subunits
Tetramers formed by 4 homologous subunits 3
Families NMDA AMPA Kainate NR1 GluR1-4 GluR5-7
NR2A-D (mostly KA1-2 NR3A-B GluR1/2
GluR2/3) obligatory
16
Ion Selectivity of Glutamate Channels
Non-NMDA Receptors With GluR2 subunit
permeable only to K and Na
predominant Without GluR2 subunit
Ca2-permeable NMDA Receptors
Permeable to K, Na, Ca2 High conductance
17
RNA Editing Determines Ca2-Permeability of AMPA
Receptors
Right Modified from Zigmond et al. (Eds.)
Fundamental Neuroscience, Sinauer (1999)
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RNA Editing DeterminesCa2-Permeability of AMPA
Receptors
Kandel, Schwartz Jessel, Principles of Neural
Science 4th Ed. (2000)
19
Isolating AMPA-R and NMDA-R CurrentsWith
Selective Blockers
Nestler, Hyman, Malenka, Molecular
Neuropharmacology McGraw-Hill (2001)
20
In this lecture, Ive described the Ligand-gated
GABA and glycine receptors, which are inhibitory.
Ive also introduced the excitatory AMPA-type
glutamate receptors.
In the next lectures, Ill discuss synaptic
plasticity in the CNS, and describe NMDA-type
glutamate receptors in detail. Ill also discuss
trafficking of AMPA and NMDA receptors.