Download Biochemistry 6/e - Personal Webspace for QMUL

Membrane Protein Channels
Potassium ions queuing
up in the potassium
channel
Pumps: 1000 s-1
Channels: 1000000 s-1
Pumps & Channels
• The lipid bilayer of biological membranes is
intrinsically impermeable to ions and polar
molecules.
• Permeability is conferred by two classes of
membrane proteins, pumps and channels.
• Pumps use an energy source (ATP or light) to
drive the thermodynamically uphill transport of
ions or molecules.
• Channels, in contrast, enable downhill or passive
transport (facilitated diffusion).
Propagation of nerve impulses
We shall examine three channels important
in the propagation of nerve impulses: the
ligand gated channel (for which the
acetylcholine receptor is the paradigm and
which communicates the nerve impulse
between certain neurons); and the voltage
gated Na+ and K+ channels, which conduct
the nerve impulse down the axon of a
neuron.
Nerve communication across synapses
• Ligand gated channel
• Acetylcholine is a
cholinergic
neurotransmitter
• 50 nm synaptic cleft
• Synaptic vesicles have
10000 acetylcholine
molecules
Nerve communication across
synapses
• Synchronous export of 300 vesicles in response to
a nerve impulse.
• Acetylcholine concentration increases from 10nM
to 0.5mM in a ms.
• The binding of acetylcholine to the postsynaptic
membrane changes its ionic permeabilities. The
conductance of Na+ and K+ increases in 0.1 ms,
leading to a large inward current of Na+ and a
smaller outward flux of K+.
Nerve communication across
synapses
• The inward Na+ current depolarises the
plasma membrane and triggers an action
potential. Acetylcholine opens a single type
of cation channel, which is almost equally
permeable to Na+ and K+.
• This change in permeability is mediated by
the acetyl-choline receptor.
Acetylcholine receptor
2a, b, g, d
Pseudo five fold
symmetry
Acetyl choline receptor - a
ligand gated ion channel
Voltage gated channels (K+ &
Na+ channels)
• The nerve impulse is an electrical signal
produced by the flow of ions across the
plasma membrane of a neuron.
• The interior of the neuron has a high
concentration of K+ and a low
concentration of Na+.
• These gradients are produced by a Na+-K+
ATPase.
Action potential – signals are send along
neurons by transient depolarization &
repolarization
Depolarization
beyond a
threshold causes
Na+ ions to flow
in leading to
further
depolarisation &
more Na+ influx
K+ ions flow
out restoring
the
membrane
potential
Causes –60 to +
30 mV in a ms
There must be specific
ion channels
Potassium & Sodium Channels
Hydrophobic except S4 – positively charged
Protein purified on the basis that it
could bind tetrodotoxin (from the
puffer fish) binds Na+ channels
with Ki ~ 1nM – lethal dose for
adult 10ng.
Structure of the potassium ion
channel
Potassium ion channel
Path through the K+ channel
Inside cell
Selectivity filter
Thr-Val-Gly-Tyr-Gly
Selectivity of K+ channel
• Ions with radius >
1.5Å are too big to fit
through the channel of
3.0Å diameter
• Na+ is not so well
solvated by the protein
Voltage gated requires substantial
conformational change
Model for activation - S1
to S4 form the voltage
responsive paddles
The channel can be
inactivated by occlusion of
the pore
“Ball and chain model”
Trypsin cleaved channel
(cytoplasmic tail) does not
inactivate. Neither does a
mutant lacking 42 Nterminal residues
Adding back the peptide 120 restores inactivation
Na+ and K+ channels work
together to give the action
potential
Na+ in first
Then K+ out