Ion channels are pore-forming membrane proteins that selectively transport ions across cell membranes. They are classified based on their gating mechanism (voltage-gated or ligand-gated), the type of ion transported, and their localization. Voltage-gated channels open and close in response to changes in membrane potential, while ligand-gated channels open when specific ligands bind. Dysfunctions in ion channels can cause diseases. Ion channels are important drug targets, and several drugs like tetrodotoxin, ziconotide, benzodiazepines, and lidocaine act by modulating specific ion channels.

1. Ion Channels
Presented by-
Aindrila Saha
Roll Number-1411009
Third Year
School of Biological Sciences
B351: Principles of Drug Designing

2. What are ion channels?

Pore forming transmembrane proteins
associated with transport of specific ions
in or out of the cell.

Highly selective in type of ion transported
(exceptions are there).

Very high rate of ion transfer.

Ions are transported across
electrochemical gradient.

Passive mechanism.

3. Discovery

Fundamental properties of channels
mediated by currents were first discovered
by Alan Hodgkin and Andrew Huxley on
their work on action potential (1952).

The existence of ion channels was
confirmed in the 1970s by Bernard Katz
and Ricardo Miledi using noise analysis.

The Nobel Prize in Chemistry for 2003
was awarded to two American scientists:
Roderick MacKinnon for his studies on the
physico-chemical properties of ion

4. Biological Roles

Conductance of Nerve impulse,
generation of action potential, synaptic
transmission.

Cardiac, skeletal and smooth muscle
contraction.

Epithelial transport of nutrients and ions.

T-cell activation (immune regulation).

Pancreatic beta cell insulin release.

5. Classification

On the basis of gating.

On the basis of type of ion passed.

Number of gates present.

Localization of proteins in the cell.

6. Classification based on gating

Voltage Gated Ion Channels
- Open and close in response to membrane
potential.

Ligand Gated Ion Channels
- Open in response to specific ligand
molecules binding to the extracellular
domain of the receptor protein.

Other Gatings
- Indirect signalling, mechano-gated ion
channels, light gated channels,

7. a) 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 soma of
the neurons.

8. Types of Voltage Gated Channels

Voltage Gated Sodium Channels (9
members, responsible for membrane
depolarization in action potential
generation)

Voltage Gated Calcium Channels (10
members,play an important role in both
linking muscle excitation with contraction
as well as neuronal excitation with
transmitter release. )

Voltage Gated Potassium Channels (40
members, role in repolarization of cell

9. Types of Voltage Gated Channels

Transient receptor potential channels
(TRP channels): 28 types, some of them
are voltage gated, named after their role
in Drosophila phototransduction.

Hyperpolarization-activated cyclic
nucleotide-gated channel ( pacemaking
channels in the heart, sensitive to cAMP,
cGMP that alter the voltage sensitivity of
the channels)

Voltage sensitive proton channels
(helps in acid extrusion from cell,

10. Structure

Several subunits with a central pore.

Ion specific, but ions with similar charge
and size can enter.

Functionality governed by 3 main parts-
the voltage sensor the pore and the gate.

Na, K and Ca channels have 4
transmembrane alpha subunits
surrounding the pore.

Six subunits: S1-S6. S1-S4: Voltage
sensing region, S5-S6: Gate and pore.


11. Structure
Fig: Subunits of a Voltage gated ion channel
Source: By Efazzari - Own work, CC BY-SA 4.0,
https://commons.wikimedia.org/w/index.php?
curid=47402794

12. Mechanism of action

13. Mechanism

For potassium channel: When a
potential difference is introduced over the
membrane, the associated electric field
induces a conformational change in the
potassium channel. The conformational
change distorts the shape of the channel
proteins sufficiently such that the cavity, or
channel, opens to allow influx or efflux to
occur across the membrane.

14. Mechanism

Voltage sensing in Na and Ca
channels: Positve charges in the voltage
sensing domain, Presence of Arginine and
histidine repeats in this segment,
conserved domain.

Gate acts as a mechanical obstruction to
ion flow.

Channel closes milliseconds after
opening.

15. b) Ligand Gated Channels

Group of transmembrane ion channels
that allow the passing of several ions
upon the binding of specific chemical
messenger like neurotransmitters.

Two domains: Transmembrane 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

16. Cys-Loop Receptors

Characteristic loop formed by a disulfide
bond between two cysteine residues in
the N terminal extracellular domain.

Provides specificity for (1) acetylcholine
(AcCh), (2) serotonin, (3) glycine, (4)
glutamate and (5) γ-aminobutyric acid
(GABA) in vertebrates.

Structural elements are well conserved,
with a large extracellular domain (ECD)
harboring an alpha-helix and 10 beta-
strands. Following the ECD, four

17. Ionotropic Glutamate Receptor

Binds to NT Glutamate.

Consists of a tetramer.

Each sub-unit consists of extracellular
amino terminal domain (ATD, which is
involved in tetramer assembly), an
extracellular ligand binding domain (LBD,
which binds glutamate), and a
transmembrane domain (TMD, which
forms the ion channel).

Each subunit of the tetramer has a binding
site for glutamate formed by the two LBD

18. ATP Gated channels

Bind to ATP in order to open.

They form trimers with two
transmembrane helices per subunit and
both the C and N termini on the
intracellular side.

19. Mechanism and Receptors

Ionotropic and Metabotropic Receptors
Source: http://www.mun.ca/biology/desmid/brian/BIOL2060/BIOL2060-
13/13_17.jpg

20. Classification on the basis of types
of ions passed

Chloride Channels

Potassium Channels (Voltage-gated
potassium channels, Calcium-activated
potassium channels , Inward-rectifier
potassium channels, Two-pore-domain
potassium channels)

Sodium Channels (Voltage-gated sodium
channels, Epithelial sodium channels)

Calcium Channels

Proton Channels (Voltage Gated Proton
Channels)

21. Classification on the basis of
Localisation

Plasma Membrane Channels : Example-
Voltage-gated potassium channels (Kv),
Sodium channels (Nav), Calcium
channels (Cav) and Chloride channels
(ClC)

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.)

22. Ion Chanel Kinetics

In electrophysiology, “Gating” refers to the
opening (activation) and closing
(inactivation) of ion channels.

Kinetics is modeled by a two state Markov
Model with alpha, the activation constant
and beta, the inactivation constant.

Single channel kinetics are mostly
recorded by Patch clamp technique.

23. Biological Implication

Action Potential Generation (Voltage
Gated Channels)
Source: http://www.vce.bioninja.com.au/aos-2-detecting-and-
respond/coordination--regulation/nervous-system.html

24. Biological Implications

Ventricular Myosite Action Potential
(Voltage Gated Channels)

25. Biological Implications

Synaptic Transmission (Voltage and
Ligand Gated Mechanisms)
Source: http://ibguides.com/images/chemical-synapse.png

26. Drugs Targetting Ion Channels

Ion Channels are varied widely and play a
wide range of critical biological functions.

55 different medical conditions have been
attributed to ion channel dysfunction.

Owing to these conditions, 13.4% of all
drugs are targetted to ion channels
(second highest after GPCRs).

Worldwide sale of ion channel drugs
(estimate) > $12 billion.
Source: Discov Med. 2010 Mar;9(46):253-60, “Targeting ion channels for drug discovery”,
Clare JJ.

27. Drugs Targetting Ion Channels

1. Tetrodotoxin

2. Ziconitide

3. Benzodiazepines

4. Conotoxin

5. Lidocaine

Other drugs are: Verapamil, Diltiazem,
Amlodipine, Nimodipine, Nifedipin,
Lidocaine etc.

Most of them are used as anaesthetics, to
cure epilepsy, treat hypertension and

28. 1. Tetrodotoxin

Source: Tetraodontiformes, an order that includes
pufferfish, porcupinefish, ocean sunfish, and
triggerfish.

Structure:
Structure of Tetrodotoxin
Molecule (Source: Wikipedia)

29. Tetrodotoxin

Pharmacological Activity : Potent
Sodium Channel blocker, Neurotoxin and
reduces drug craving and anxiety in
abstinent heroin addicts.

Biomolecular Target: A partuicular type
of fast acting Sodium Channel.

Mechanism of Action: Binds to the site 1
f a specific Volage gated fast opening
sodium channel and temporarily blocks
the functioning of the channel. TTX-Na+-s
(present in most part of the body) and

30. 2. Ziconitide

Source: Cone snail Conus magus.

Structure: Ziconotide is a peptide with the amino
acid sequence H-Cys-Lys-Gly-Lys-Gly-Ala-Lys-Cys-Ser-
Arg-Leu-Met-Tyr-Asp-Cys-Cys-Thr-Gly-Ser-Cys-Arg-
Ser-Gly-Lys-Cys-NH2.

31. Ziconitide

Pharmacological activity: Potentic
analgesic with 1000 times the potency of
Morphine.

Biomolecular target: Specific CaN
channel.

Route of administration: Intrathecally

Mechanism of Action: a selective N-
type(neuronal type) voltage-gated calcium
channel blocker. This action inhibits the
release of pro-nociceptive neurochemicals
like glutamate, calcitonin gene-related

32. 3. Benzodiazepines

Structure: Fusion of a benzene ring with
a diazepine ring.
Source: By Jü - Own work, CC BY-SA
4.0,https://commons.wikimedia.org/w/index.php?curid=49864697

33. Benzodiazepine

Pharmacological activity: Acts as
sedative, hypnotic, anxiolytic,
anticonvulsant, muscle relaxant, used to
treat a variety of indications such as
alcohol dependence, seizures, anxiety
disorders, panic, agitation, and insomnia.

Mechanism of Action: Activates
inhibitore neurotransmitter GABA, acts as
a positive allosteric modulator of GABAa
receptor by increasing the total conduction
of chloride ions across the neuronal cell
membrane when GABA is already bound

34. Benzodiazepine

Side effects: Generally considered safe
for short term use but have withdrawal
effects due to long term use. Prescribing
during pregnancy is controversial. Elderly
at increased risk of short and long term
effects.

35. 4. Conotoxin

Source: Derived from different species of
cone snail (Genus: Conus).

Structure: Peptide with 30-40 amino acid
residues and 1-2 disulphide bonds.
Source: By Fvasconcellos (talk ·
contribs) - From PDB entry
1AKG., Public Domain,
https://commons.wikimedia.org/w/
index.php?curid=4286936

36. Conotoxin

Biomolecular target: Different varieties
of conotoxin affects different ion channels
and receptors.
α-conotoxinc - inhibits nicotinic
acetylcholine receptors at nerves and
muscles.
δ-conotoxin - inhibits the inactivation of
voltage-dependent sodium channels.
κ-conotoxin- inhibits potassium channels.
μ-conotoxin -inhibits voltage-dependent
sodium channels in muscles.

37. Conotoxin

Mechanism of action and
Pharmacological activity: ω-conotoxin
has an analgesic effect and ω-conotoxin
M VII A is 100 to 1000 times that of
morphine. Synthetic version used as
analgesic.

38. 5. Lidocaine

Structure: 2-(diethylamino)-N-(2,6-
dimethylphenyl)acetamide
Source: By Ben Mills -
Own work, Public
Domain,
https://commons.wikim
edia.org/w/index.php?
curid=5750147

39. Lidocaine

Pharmacological Activity: Local
anaesthetic with rapid onset of action and
immediate response, important class-1b
antiarrhythmic drug, topically used for
neuropathis pain.

Bioavailalbility: 35% (oral), 5% (topical).

Mechanism of Action: Voltage
dependent fast sodium channel blocker,
prevents polarization of post synaptic
membrane and signal conduction.

40. Ion Channel dysfunction and
Diseases

Channelopathies

Cystic fibrosis is caused by mutations in
the CFTR gene, which is a chloride
channel.

Brugada syndrome is another ventricular
arrhythmia caused by voltage-gated
sodium channel gene mutations.

Shaker gene mutations, ataxia etc.

41. THANK YOU!