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The Structure of Ion
Channels
Ion channels
Classification by gating
Voltage-gated channels
Voltage-gated Na+, Ca2+ , K+ channels
Classification by selectivity
Na+ channels
Ca2+ channels
Transient receptor potential (TRP)
channels
K+ channels
Cyclic nucleotide-gated channels
H+ channels
Ligand-gated channels
Ionotropic receptors
ATP-sensitive channels
Cl- channels
Anion channels
Cation channels
Cyclic nucleotide-gated channels
Inward rectifiers
Light-gated channels
Mechanosensitive channels
Gap junctions
Ligand-gated ion channels
Cys-loop receptors
GABAA receptors
Anion selective
Glycin receptors
nACh receptors
Serotonin Receptors
Ionotropic glutamate receptors
Hyperpolarization activated cyclic
nucleotide-gated channels
ATP-sensitive potassium channels
Cation selective
Ligand-gated ion channels → Cys-loop receptors → general structure
Ligand-gated ion channels → Cys-loop receptors → general structure
5-fold rotational symmetry
Ligand-gated ion channels → Cys-loop receptors →
Ligand-gated ion channels – Cys-loop receptors
General
structure
Extracellular
General
structure –→
Extracellular
domaindomain
Ligand binding site
Allosteric modulator
binding site
Ligand binding site
Ligand-gated ion channels → Cys-loop receptors →
Ligand-gated ion channels – Cys-loop receptors
General
structure
Extracellular
General
structure –→
Extracellular
domaindomain
• the „binding pocket” is formed by
one principal and one
complementary subunit
• Binding pocket residues:
• A, B, C loops from the principal
subunit
• D, E, F β-sheets from the
complementary subunit
• 2 bindings sites are required for
channel activation
• ECD contracts around agonists,
relaxes around antagonists
• cation-π interactions
Ligand-gated ion channels → Cys-loop receptors →
General structure → Transmembrane domain
M1: may be involved in transmitting movements from ligand-bound ECD to M2
M2-M3 loop: critical role in transmitting the energy of binding into channel opening
M2: provides pore-lining residues, constitutes the gate
M3 and M4: shield M2 from the lipid environment
Ligand-gated ion channels → Cys-loop receptors →
General structure → Transmembrane domain
Hydrophobic girdle
Ion selectivity filter
hydrophobic
charged
Anionic channels
(GABAA, Gly-R)
Cationic channels
(nACh-R, 5-HT-R )
-1` position: Glutamic
acid
-1` position:
uncharged
Ligand-gated ion channels → Cys-loop receptors →
GABAA receptors → Subunits
Class
IUPHAR protein name
Gene
α1
GABRA1
α2
GABRA2
α3
GABRA3
α4
GABRA4
α5
GABRA5
α6
GABRA6
β1
GABRB1
β2
GABRB2
β3
GABRB3
γ1
GABRG1
γ2
GABRG2
γ3
GABRG3
delta
δ
GABRD
epsilon
ε
GABRE
pi
π
GABRP
theta
θ
GABRQ
ρ1
GABRR1
ρ2
GABRR2
ρ3
GABRR3
alpha
beta
gamma
rho
GABA is the most common
neurotransmitter in the CNS
GABAA receptors found in 40% of
synapses in the brain
GABA-R classes:
GABAA: ionotropic
GABAB: G-protein-coupled
There are 19 different GABA-R receptor
subunits
Most abundant subunit classes:
alpha, beta, gamma, delta
(rho is expressed in the retina)
GABAA is anion selective
Ligand-gated ion channels → Cys-loop receptors →
GABAA receptors → Subunit stoichiometry
two different α and two different β
subunits can be present
ϒ cannot be precipitated with other
ϒsubunits
δ is not present with ϒ
2 α, 2 β and 1 ϒ or δ subunits make up
the channel
estimated number of different subtypes:
800
•α1 - β2 - ϒ2 is the most common
composition
α2βγ2, α3βγ2, α4βγ2, α5βγ2, α6βγ2,
α4βδ and α6βδ are also common to
lower extent
a
Ligand-gated ion channels → Cys-loop receptors →
GABAA receptors → Allosteric modulaMon
BZ1 class: contain the α1 subunit
cortex, talamus, cerebellum
sedative, amnesia
BZ2 class: contain the α2 subunit
limbic system, motor neurons
anxiolytic, myorelaxant
Ligand-gated ion channels → Cys-loop receptors →
Glycine receptors
Gly is one of the most common
neurotransmitter in the CNS
Gly-R is anion selective
5 known subunits:
α 1 – 4 and β
Developmental switch of isoforms:
fetal form α2 homomers
adult form: α1β heteromers
Subunit stoichiometry:
3α:2β
long-held dogma, no evidence
Ligand-gated ion channels → Cys-loop receptors →
Nicotinic Acetylcholine Receptors
Cys-loop receptor signature structure
Ligand-gated ion channels → Cys-loop receptors →
Nicotinic Acetylcholine Receptors
nACh-R is a cation channel
17 known subunits:
α 1 – 10
β1 – 5
δ
ϒ
ε
Na+ (inward) and K+ (outward) ions
flow through the open channel, net
current is inward (depolarizing)
Muscle type nAChR (neuromuscular junction):
α1, β1, γ, and δ – embryonic
α1, β1, δ, and ε - adult
2:1:1:1 ratio
Neural type nAChR (central or peripheral
nervous system):
homo- or heteromeric
combinations of α2−α10 and β2−β4
subunits
e.g. (α4)3(β2)2, (α4)2(β2)3, (α7)5
Ligand-gated ion channels → Cys-loop receptors →
Ionotropic Serotonin Receptors
Serotonin: 5-hydroxitryptamine
5-HT receptors
Family
Type
Mechanism
5-HT1
Gi/Go-protein coupled.
Decreasing cellular levels of cAMP.
5-HT2
Gq/G11-protein coupled.
Increasing cellular levels of IP3 and DAG.
5-HT3 Ligand-gated Na+ and K+ cation channel.
Depolarizing plasma membrane.
5-HT4
Gs-protein coupled.
Increasing cellular levels of cAMP.
5-HT5
Gi/Go-protein coupled.
Decreasing cellular levels of cAMP.
5-HT6
Gs-protein coupled.
Increasing cellular levels of cAMP.
5-HT7
Gs-protein coupled.
Increasing cellular levels of cAMP.
5 genes encoding for 5 subunits
HTR3A
5-HT3A
HTR3B
5-HT3B
HTR3C
5-HT3C
HTR3D
5-HT3D
HTR3E
5-HT3E
Potential
Inhibitory
Excitatory
Excitatory
Excitatory
Inhibitory
Excitatory
Excitatory
Ligand-gated ion channels → Glutamate Receptors (no Cys-loops here)
Nervous system: Glutamate is the main excitatory
neurotransmitter, present in 50% of nervous tissue
Glutamic Acid
Taste buds: GluR is responsible for the transmission of the umami taste stimuli
Clinical conditions:
Autism
Attention Deficit Hyperactivity Disorder (ADHD)
Diabetes
Multiple sclerosis
Schizophrenia
etc.
Ligand-gated ion channels → Glutamate Receptors
Ionotropic
Metabotropic
AMPA receptors
Kainate receptors
NMDA receptors
GluA1-4
GluK1-5
GluN
9 isoforms
Homo- or
heteromers
GluK1-3: homo- or
heteromers
(GluN1)2
+
(GluN2)2
or
GluN1 + GluN2
GluK4-5: “silent
subunits”
Four subunits assemble in one channel
mGluR
Ligand-gated ion channels → Glutamate Receptors
ATD: amino-terminal domain
LBD: ligand binding domain
TMD: transmembrane domain
CTD: carboxy-terminal domain
Ligand-gated ion channels → Glutamate Receptors
Tetrameric structure
Ligand-gated ion channels → Glutamate Receptors
Dimer of dimers!
Same polypeptide
Different
conformations!
Ligand-gated ion channels → Glutamate Receptors
Ligand-gated ion channels → Glutamate Receptors
Ligand binding-induced
conformation changes
Voltage-gated ion channels → General membrane topology
Inward rectifiers
Tetrameric structure
Membrane topology of one subunit
Inward rectifiers
2
1
3
0
AP
4
4
Is it an inward current?
IK1
“Linear” current-voltage relationship
Blockade by cytoplasmic Mg2+
and polyamines
Inward rectifiers and voltage-gated channels → Ion selectivity
Conserved selectivity filter motif
Voltage-gated ion channels → General membrane topology
Voltage-gated ion channels → Conformation transitions
Closed
Open
Closed
Open
Inactivated
N-type inactivation
C-type inactivation
Voltage-gated ion channels → Conformation transitions →
Various kinetics contributes to functional diversity
Six TMD structure
Transient outward current
Delayed rectifier current
2
2
1
1
3
3
0
0
4
mV
5050mV
-35mV
mV
-35
-80mV
mV
-80
4
4
50mV
-40mV
4
Voltage-gated ion channels → Auxiliary subunits
The minK story
The cardiac delayed rectifier
KvLQT1 drives no current in
homomeric form
A single TMD protein called minK
was injected into Xenopus
oocytes → huge delayed rectifier
potassium current is generated.
How is that possible?
Voltage-gated ion channels → Auxiliary subunits
Molecular toolkit: the KCNE gene family
KCNE genes
KCNE1 - minK
KCNE2 – MiRP1
KCNE3 – MiRP2
KCNE4 – MiRP3
KCNE5 – MiRP4
Voltage-gated ion channels → Auxiliary subunits
Molecular toolkit: the KCNE gene family
KvLQT1 + minK
KvLQT1 + MiRP2
KvLQT1 + MiRP4
Voltage-gated ion channels → Diversity of potassium channels
Voltage-gated ion channels → Sodium channels
“Tetramer”-mimicking structure
2
1
3
0
4
4
All encoded by a single giant polypeptide
Voltage-gated ion channels → Calcium channels
α2δ subunit
β subunit
Increased traficking
Increase current amplitude
Left-shifted voltage dependence of
activation
Faster activation and inactivation
Left-shifted voltage dependence of
inactivation
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