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
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?

4
GABA Receptor Subunit Composition
GABA receptors usually contain at least one each
of ?, ?, and ? subunits.
A typical subunit composition
Katzung (Ed.) Basic Clinical Pharmacology,
Lange (2004)
5
Model for nAChR Gating Twisting of M2 Helices
Polar Ser or Thr (Selectivity Filter)
Hydrophobic Leu (Gate)
Modified from Zigmond et al. (Eds.) Fundamental
Neuroscience, Sinauer (1999)
6
Ion Selection Cationic Channels
(for contrast)
Modified from Keramidas et al., Prog. Biophys.
Mol. Biol. 86 161 (2004)
7
Ion Selection Chloride Channels
Modified from Keramidas et al., Prog. Biophys.
Mol. Biol. 86 161 (2004)
8
GABA-R Predicted Interaction Between Cys Loop
and TM2-TM3 Linker
Kash et al., Nature 421 272 (2003)
9
Gating of GABA Channels InteractionBetween the
Cys-Loop and the TM2-TM3 Linker
K279 in linker D149 in loop
Kash et al., Nature 421 272 (2003)
10
Pharmacology of Inhibitory Receptors
GABA agonists
Benzodiazipines Valium (diazepam) Ambien
(zolpidem, short acting)
Barbiturates Phenobarbital Secobarbital
(Seconal)
11
Benzodiazepines and Barbiturates EnhanceGABAA
Currents Through Different Mechanisms
Probability of Opening
Open Time
Twyman et al (1989) Ann. Neurol. 25 213-220
(1989)
12
GABA and Glycine Antagonists
GABA antagonists Bicuculline
picrotoxin
Glycine antagonist Strychnine
13
Receptors are clustered at postsynaptic sites by
specialized molecular scaffolds
14
Clustering of Receptors at the Postsynaptic
Membrane
The Neuromuscular Junction
From Banks, Froehner et al. J. Neurocytol. 32,
709 (2003)
15
Clustering of Receptors at the Postsynaptic
Membrane
Glycine and GABA receptors (inhibitory junctions)
From Kneussel and Loebrich, Biol. Cell 99, 297
(2007)
16
I will return to the scaffold for glutamate
receptors (called the postsynaptic density) in
later lectures.
17
Topology of Glutamate Receptors
Kandel, Schwartz Jessel, Principles of Neural
Science 4th Ed. (2000)
18
Ionotropic Glutamate Receptor Subunitsare
Tetramers formed by 4 homologous subunits
3 Families NMDA AMPA Kainate
NR1 GluR1-4 GluR5-7
NR2A-D (most are KA1-2 NR3A-B
GluR1/2 or GluR2/3) obligatory
19
Ion Selectivity of Glutamate Receptor Channels
AMPA and Kainate Receptors With GluR2
subunit permeable only to K and Na
Without GluR2 subunit Ca2-permeable NMD
A Receptors Permeable to K, Na, Ca2
relatively High conductance
20
RNA Editing Determines Ca2-Permeability of AMPA
Receptors
Right Modified from Zigmond et al. (Eds.)
Fundamental Neuroscience, Sinauer (1999)
21
RNA Editing DeterminesCa2-Permeability of AMPA
Receptors
Kandel, Schwartz Jessel, Principles of Neural
Science 4th Ed. (2000)
22
Isolating AMPA-R and NMDA-R CurrentsWith
Selective Blockers
Nestler, Hyman, Malenka, Molecular
Neuropharmacology McGraw-Hill (2001)
23
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 and scaffolding of AMPA and NMDA
receptors.