1 Ion Channel - Pertemuan 8-Mhs

Ion Channels :
Site of drug action
Heny
Ekowati
ION CHANNELS
 Highly selective in type of ion
transported (exceptions are there).
 Very high rate of ion transfer.
 Ions are transported across

electrochemical gradient.
 Passive mechanism.
Ion channels are pore-forming membrane proteins whose function is

- Establishing a resting membrane potential,
- Shaping action potentials and other electrical signals by gating the flow of
ions across the cell membrane,
- Controlling the flow of ions across membranes,
- Regulating cell volume.
Their activation translates into a rapid physiological effect.
ION CHANNELS: general concepts
Channels differ with respect to the ion they let pass (Na+, K+, Ca++, Cl−).
The ion channel selectivity discriminates cations (Na, K, Ca) from anions (Cl),
and allow selectivity among cations (Na, K, Ca).
Classificatio
n

1. On the basis of gating.

2. On the basis of type of
 ion passed.
 3. Localization of proteins
in the cell.
Classification based
on gating
1. Voltage Gated Ion Channels
Open and close in response to

membrane potential.
2. Ligand Gated Ion Channels (Ligand
Gated ion Channel receptor)

Open in response to specific ligand

molecules binding to the extracellular
domain of the receptor protein.
3. Other Gatings

Indirect signalling, mechano-gated ion

channels light gated channels.
Voltage Gated Ion

Channels
Voltage sensitive

 Conformational change in response

to the potential gradient.

 Generally ion specific.


 Important for excitable cells like

neurons.

 Role in regulation of depolarization


and polarization of neuronal

membrane during an action
potential.

 Distributed along the axon and

VOC CHANNELS
Electrophysiological studies indicate the existence of three main types of VOC (K+,
Na+, Ca2+ channels). In number of neurons various subtypes of Ca2+ channels (P, T,
N and L-type) occur together.
Na+ channels
Ca++ channels
K+ channels
VOC CHANNELS
In each protein subunit, the membrane-spanning segments, designated S1-
S6, all take the form of alpha helices with specialized functions.
The S1-S4 TMS serve as the voltage-sensing region.
The S5-S6 TMS and pore loop have a key role in ion conduction, and
represent the gate and pore of the channel.
S1-4
Voltage –sensing S5-6
region Pore region
S1 S6
S4 C- terminal
N- terminal
VOC CHANNELS: state of activity
A voltage gated ion channel can be in three states: closed, open or inactivated.
The inactive state, which is stable and non-conducting, is caused by the physical
blockage of the pore. The blockage is caused by a “ball” of amino acids attached
to the main protein by a string of residues on the cytoplasmic side. The ball enters
the open channel and binds to the hydrophobic inner vestibule at the center of
the channel.
The blockage causes inactivation of the channel by stopping the flow of ions.
Ligand Gated Ion
Channels
 Group of trans membrane ion channels

the passing of several ions that allow

upon the binding of specific chemical
messenger like neurotransmitters.
 Two
domains: Trans-membrane
domain including channel pore;
Extracellular domain including ligand
binding site.

 Function: Conversion of presynaptic

chemical signal quickly and effectively
into post-synaptic electreical signal.
 Three super families: cys-loop

Ligand-gated ion channel receptor or
Receptor-operated (ROC) CHANNELS
•PERMEABILITY to CATIONS LIGAND RECEPTOR

(Na+, Ca++, K+)
Acetilcholine Nicotinic R
Ion entry produces Glutamate and other excitatory NMDA R

aa AMPA R
DEPOLARIZATION KAR
(cell activation)
Serotonin 5-HT3 R
ATP and purines P2X
Ciclic nucleotides CNG

(cAMP and cGMP)
• PERMEABILITY to ANIONS LIGAND RECEPTOR

(Cl-)
Ion entry produces GABA GABAA
HYPERPOLARIZATION Glicine Gly R
(cell inhibition)
Voltage-operated (VOC) CHANNELS
The function of VOC is closely dependent on transmembrane electrochemical
gradient. A gradient is represented by the different concentration of ions on
either side of the membrane. The open conformation of the ion channel allows
for the translocation of ions across the cell membrane, while the closed
conformation does not. The activity of these channels is connected with the
activity of enzymes and the processes of phosphorylation of membrane proteins.
Post-synaptic membrane Muscle membrane

with ROC’s with VOC’s
Classification on the basis of
types of ions passed
1. Chloride Channels

2. Potassium Channels (Voltage-gated


potassium channels, Calcium-activated

potassium channels , Inward-rectifier
potassium channels, Two-pore-domain
potassium channels)
3. Sodium Channels (Voltage-gated

sodium channels, Epithelial sodium

channels)

4. Calcium Channels

5. Proton Channels (Voltage Gated

Classification on the basis of
types of localization

 Plasma Membrane Channels :

Example: Voltage-gated potassium
channels (Kv), Calcium channels (Cav),
Chloride channels (CIC)
 Intracellular

Channels
Example : Endoplasmic Reticular channels
(RyR, SERCA, ORAi) and Mitochondrial
channels (mPTP, KATP, BK, IK, CLIC5, Kv7.4
at the inner membrane and VDAC and
CLIC4 as outer membrane channels.)
Potensial sel
• Depolarisasi
• Repolarisasi
• Hiperpolarisasi
• Resting potensial
Na+ Channel
Sodium Channels - Structure
 Composed of α, β-1 and β-2 subunits, but the large
α-subunits carries most of the functional properties
 4 repeated motifs, each with 6 transmembrane
domains
 All linked together
 Contain a voltage “sensor”/ligand binding domain
(method of activation)
 The hydrophobic S4 segment (voltage “sensor”) is
found in all voltage gated Na+ channels and is
absent in ligand gated Na+ channels
 Selectivity filter (shell of hydration)
 Inactivation gate
Cartoon representation of the “typical” voltage-activated
sodium channel
Na + Channel
Blockers/Pharmacological Agents
 Tetrodotoxin (TTX)
 Amiodarone
 Lidocaine
 Procainamide
 Mexilitine
 Ketamine
 Many, many others
K Channels
+
K+ CHANNELS
K+ channels are found in virtually all living organisms. They form K+ -selective pores
that span cell membranes and conduct rapidly and selectively K+ ions down their
electrochemical gradient.
These channels act to set or reset the resting potential in many cells.
Voltage-gated K+ channels
Calcium-activated K+ channels
Inward rectifier K+ channels “Leak” or background K+ channels

Ca2+ Channel
Cl- Channel
Obat pada Kanal Ion Cl-
 Lubiproston (Amitiza ®), mengaktifkan
kanal ClC-2 sehingga meningkatkan
sekresi cairan ke lumen usus.
 Obat ini diindikasikan untuk mengatasi
obstipasi kronis idiopatik
SEE YOU NEXT WEEK
THANK YOU

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Ion Channels :

Site of drug action

 Very high rate of ion transfer.

 Ions are transported across

Ion channels are pore-forming membrane proteins whose function is

Open in response to specific ligand

Indirect signalling, mechano-gated ion

 Conformational change in response

 Generally ion specific.

 Important for excitable cells like

 Role in regulation of depolarization

and polarization of neuronal

 Distributed along the axon and

the passing of several ions that allow

 Function: Conversion of presynaptic

•PERMEABILITY to CATIONS LIGAND RECEPTOR

Ion entry produces Glutamate and other excitatory NMDA R

Ciclic nucleotides CNG

• PERMEABILITY to ANIONS LIGAND RECEPTOR

Post-synaptic membrane Muscle membrane

2. Potassium Channels (Voltage-gated

potassium channels, Calcium-activated

sodium channels, Epithelial sodium

5. Proton Channels (Voltage Gated

 Plasma Membrane Channels :

Inward rectifier K+ channels “Leak” or background K+ channels

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