ion channels as drug target
TRANSCRIPT
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)