Transcript A Neurosurgical Operation

Ion Channels
The plasma membrane is 6-8nm thick, and
consists of a mosaic of lipids and proteins. The
lipid is hydrophobic, and will not allow ions
through.
Ions are surrounded by waters of hydration. To
move through the hydrophobic lipid bilayer,
water molecules would need to be stripped off
the ion. This takes too much energy.
Ion Channels
The solution is to provide ions with specialized
pathways such as ion channels that will permit
ions to cross with most or all of their water
molecules.
Ion channel pores therefore provide ions with a
polar environment.
Structure of
Ion Channels
Ion channels are large
assemblies of
proteins, which make
up subunits, which
combine to form
functional channels.
K+ Channels:
Shaker K+
Channel:
•Each Channel is made of 4
Subunits.
•Each Subunit is made up of
a large protein having 6
trans-membrane segments
(S1-S6).
•Between S5 and S6 there is
a loop (red) that, along
with the S6 segment, lines
the conduction pore.
Shaker K+ Channel:
What they look like:
What they look like:
Important features:
1. Gating (opening and closing)
•
What are the features that cause the channel to
open and close?
2. Ion selectivity
•
Why does a K+ channel not allow Na+ through?
3. Molecular features related to their function.
•
What are the structural features that determine the
function of the channel?
Gating
•
What are the features that cause the channel to open
and close?
Gating:
Ligands
Phosphorylation
Controlled
by different
types of
stimuli:
Voltage
Stretch
3 modes of gating:
Gating
• Involves conformational
changes in the ion channel
protein.
• Each channel protein has two
or more conformational states
(e.g., open & closed) that are
relatively stable.
• Each stable conformation
represents a different
functional state.
Voltage-Gated Ion Channels
CLOSED
OPEN
Voltage-Gated Ion Channels
A class of ion channels gated (opened and closed) by
the trans-membrane potential difference (voltage).
There are many, many, types. Among these are:
-Na+ Channels
-K+ Channels
-Ca2+ Channels
-Cl- Channels.
There are actually many types
of Na, K, Cl, and Ca Channels,
classified according to
pharmacology, physiology, and
more recently- molecular
structure.
Voltage-gated ion channels
Involved in:
1. Initiation and propagation of action potentials
2. Control of synaptic transmission
3. Intracellular ion homeostasis
4. Other aspects of intracellular function
•
Acting as activators of intracellular enzymes
•
Coordinating signals between cell membrane and
internal organelles (e.g., mitochondria).
Ligand-Gated Ion Channels
Typically, these are ion channels located on the postsynaptic
(receiving) side of the neuron
Some act in response to a secreted (external) ligandtypically a neurotransmitter such as
• Acetylcholine (Ach)
• GABA
• Glycine
• Glutamate
Some act in response to internal ligands such as cGMP and
cAMP, and are also regulated by internal metabolites such
as phosphoinositides, arachidonic acid, calcium.
Ligand-Gated Ion Channels
Among the first ligand-gated channels to be thoroughly
characterized and cloned is the Ach channel.
•5 subunits, each made of 4 membrane-spanning components (M1-M4)
•2 Ach molecules need to bind in order to open the channel pore.
•Fluxes Na and K.
Glutamate Receptors:
An important class of ligand-gated receptors because:
Glutamate is the main excitatory neurotransmitter in the
CNS
Glutamate receptors include
• Ionotropic receptors  Receptors gating a channel
whose ligand is glutamate
• Are the NMDA, AMPA & Kainate receptors as
defined by these ligands (more later).
• Metabotropic receptors  glutamate receptors that
trigger intracellular 2nd messenger systems.
Ion Selectivity:
0.095 nm
• Why does a K+ channel not allow Na+
through?
0.133 nm
Ion Selectivity:
• Why does a K+
channel not allow
Na+ through?
Concept of waters of hydration:
Increase the effective diameter of
the Na+ ion.
Thus: Pore Size is 1 mechanism for
selectivity.
Ion Selectivity:
Channels have a specialized
region that acts as a molecular
sieve  The SELECTIVITY
FILTER.
This is where an ion sheds its
waters of hydration & forms a
weak chemical bond with
charged or polar amino acid
residues that line the walls of
the channel.
So why does an Na
channel exclude K?
Molecular features related to function
•
What are structural features that determine the
function of the channel?
•
Gating
•
Ion Selectivity
Ion Selectivity:
K Channel
Pore structure:
Ionic interactions
that “stabilize”
certain ions
preferentially
K+ Channel
Two mechanisms by
which the K+ channel
stabilizes a cation in the
middle of the
membrane. First, a
large aqueous cavity
stabilizes an ion (green)
in the otherwise
hydrophobic membrane
interior. Second,
oriented helices point
their partial negative
charge (carboxyl end,
red) towards the cavity
where a cation is
located.
Ion selectivity:
Is sometimes dependent on a
single amino acid located in
the critical channel-forming
segment.
In AMPA receptor GluR2
subunits:
Glutamine –permeability to Ca
Arginine – No Ca Permeability
Interaction of GluR2 subunit with kainate
Ion selectivity & human disease:
An understanding of the principles of ion selectivity has led
to some molecular theories of human disease.
FOR EXAMPLE:
The GluR2 Hypothesis of delayed neuronal death in
cerebral ischemia
Whereby certain brain neurons exposed to transient
ischemic challenges die because they fail to express the
GluR2 AMPA receptor subunit, which governs Capermeability. Increased Ca permeability causes neurons
to die (much more about this later)
Gating: K+ Channel
Changes in voltage are sensed by charged groups in transmembrane
segments. Most of the sensing is done by the outermost positive charges
(blue) of the S4 segment although one negative charge (red, E293) of the
S2 segment is also contributing
Gating
The green shaded region represents the low
dielectric region of the channel. The charges are
accesible to the inside or to the outside, depending
on the membrane potential.
At resting (negative) membrane
potential, the positive charges of S4 are
attracted to the interior
At more positive potentials,
they are attracted to the
extracellular side.