Dr Ranjita Santra (Dhali)

Assistant Professor
Department of Clinical & Experimental Pharmacology
Calcutta School of Tropical Medicine
Exceptions: Colchicin (acts on tubulin), Cyclosporin (acts via immunophillins), etc.
Ion channels are pore-forming membrane
proteins whose functions include 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 secretory and epithelial cells, and
regulating cell volume
 Schematic diagram of an
ion channel
 1 -channel domains(typically
four per channel), 2 - outer
vestibule, 3 - selectivity
filter, 4 - diameter of
selectivity filter, 5 -
phosphorylation site, 6 -cell
membrane.
 Ionchannels are considered to be one of the
two traditional classes of ionophoric
proteins, with the other class known as ion
transporters (including the sodium-potassium
pump, sodium-calcium exchanger,
and sodium-glucose transport proteins,
amongst others)

 Potassium channels form most abundant &

diverse class of ion channels
 Study of ion channels (channelomics) often includes
biophysics, electrophysiology & pharmacology,
utilizing techniques including voltage clamp, patch
clamp, immunohistochemistry, X-ray fluorescence,
and RT-PCR.
 There are two distinctive features of ion channels that
differentiate them from other types of ion transporter
proteins:
 The rate of ion transport through the channel is
very high (often 106 ions per second or greater)

 Ions pass through channels down their

electrochemical gradient, which is a function of
ion concentration and membrane potential,
"downhill",without the input (or help) of metabolic
energy (e.g. ATP, co-transport mechanisms,
or active transport mechanisms)
 Voltage gated ion channels

 Ligand gated ion channels

 Voltage-gated channels:
 Gating: controlled by membrane
repolarization/depolarization

 Selectivity: Na+, K+ or Ca+ ions

 Intracellular ligand-gated channels:

 Ca controlled K channel
+ +

 ATP-sensitive K channel
+

 IP3-operated Ca+ channel (in the ER

membrane)
 Carbamazepine
 Phenytoin
 Lamotrigine
 Topiramate
 TCAs
 Lignocaine
 Mexiletine
 A-803467
 Benzazepinone
 Ambroxol(NW-1029)
 Lacosamide
 CDA54
HOW DO DRUGS WORK BY BLOCKING ION CHANNELS?
KEY CONCEPTS:

• Ion channels allow ions to transverse the cell membrane

through a pore and down an electrochemical gradient.

• Some drugs bind to ion channels and physically

block the pore or cause an allosteric change
that closes the pore.

• Changes in the intracellular concentration of ions mediates

the effects of inhibitors of ion channels.
 CALCIUM CHANNELS
• Extracellular compartment: (predominantly in nerve, cardiac and
smooth muscle cells)
Three types of plasma-membrane localized calcium channels:

– Voltage operated calcium channels:

Action potental depolarizes plasma membrane, which results in the
opening of “voltage” dependent calcium channels (channels can
be opened by increase in extracellular K+).

Each channel protein has four homologous domains, each

containing six membrane spanning -helices (the fourth one
functions as the “voltage” sensor.
BIMM118
 CALCIUM CHANNELS
Three types:
Type Properties Location/Function Blockers

Plasma membrane of many cells; main

High activation threshold; Dihydropyridines;
L Ca++ source for contraction in smooth and
slow inactivation verapamil; diltiazem
cardiac muscle

Low activation threshold; Main Ca++ source for transmitter release w-Conotoxin
N slow inactivation by nerve terminals (snail venom)

Low activation threshold; Widely distributed; important in cardiac Mibefradil; (verapamil;

T fast inactivation pacemaker and Purkinje cells diltiazem)

– Ligand gated calcium channels:

Calcium channels opened after ligand binding to the receptor (e.g.
glutamate/NMDA receptor; ATP receptor; nicotinic ACh receptors (
muscarinic ACh receptors signal through G-Proteins
--> slower), prostaglandin receptors

– Store operated calcium channels:

Activated by emptying of intracellular stores, exact mechanism
BIMM118

unknown
 Levocromakalim

 Bimakalim

 Rilmakalim
 Mibefradil
 Phenytoin
 Zonisamide
 Penfluridol
 Amiloride
 Valproate
 Pimozide
 Encoded by 9 genes- CLCN1- CLCN9
 Myotonia congenita (MC) was the first human disease
proven to be caused by an ion channel defect, thus
leading to the discovery of the CLCN1 gene encoding
the ClC-1 channel responsible for the high Cl
conductance of skeletal muscle membrane
 Blockers – under development
 Openers – Lubiprostone, approved by US FDA for
chronic constipation
 CLC openers- useful for hereditary channelopathies &
epilepsies
 In vitro study – ACTZ, intracellular biochemical
pathways
 The -aminobutyric acid and glycine receptors
(GABA-A and GlyR) are the major inhibitory
neurotransmitter-gated receptors in the CNS
 After neurotransmitter binding, the ingress of Cl ions
within the cell hyperpolarizes the postsynaptic
membrane, resulting in neurotransmission inhibition
 No therapeutic ligands –- GlyR
 BZDs & Phenobarbital – Epilepsies
 Drugs acting on B3 subunit of GABA-A receptor -
Chronic Insomnia
 Alpha1 & Gamma 2 mutations (GABA-A receptor) -
BZDs
 Nicotinic ACh receptors, glutamate receptors,
and serotoninergic receptors
 No effective NAch receptor modulator till now
in epilepsy & channelopathies
 Glutamate antagonists – AD, PD, HC, ALS,
melanoma, neutopathic pain
 HT3 receptor channel – antinociception &
antiemetics
 Glutamate agonists – Schizophrenia (proposed)