ion channels as drug target

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.

Ion channels 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 membranerepolarization/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 ERmembrane)

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.

BIM

M118

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.

BIM

M118

CALCIUM CHANNELS

– 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

unknown

Type Properties Location/Function Blockers

LHigh activation threshold;

slow inactivation

Plasma membrane of many cells; main

Ca++ source for contraction in smooth and

cardiac muscle

Dihydropyridines;

verapamil; diltiazem

NLow activation threshold;

slow inactivation

Main Ca++ source for transmitter release

by nerve terminals

w-Conotoxin

(snail venom)

TLow activation threshold;

fast inactivation

Widely distributed; important in cardiac

pacemaker and Purkinje cells

Mibefradil; (verapamil;

diltiazem)

Three types:

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)