RESUME

DRUG TARGET 2

VOLTAGE-GATED ION CHANNEL AND TRANSPORTER

Name : Ikvini Maulaya

NIM : 20613206

VOLTAGE-GATED ION CHANNEL

ION CHANNELS AND TRANSPORTERS

Ion channels are targets of several drug classes which are widely used in cardiology,
neurology, endocrinology, anesthesiology and other therapeutic fields. The therapeutic and
toxic effects of a particular drug class can be predicted based on their pharmacological
profile on specific ion channels. Thermodynamically, the mechanism of transmembrane
transport is divided into two types, namely active where it flows from high potential to the
low side whether using ion channels or facilitated transportes. Ion channels are
responsible for generating and regulating the electrical signals necessary for the coordinated
contraction of skeletal muscles, hormone secretion and neurotransmitter release; moreover,
in all cells, they control cell volume and motility. It contains aqueous pores through which
permeated ions can flow at very high rates (>106 /s, close to the rate of diffusion in water),
thereby generating significant currents that can rapidly change the resting membrane
potential of a cell. The difference between ion channels and transporters is in ion channels
the ion diffuses through the pore and one gate while the transporters are guarded by two
gates at minimum.

There are two primary traits characterizing the activity of the specific ion channel,
namely the mechanism that powers the gate and the ionic species which pass beyond the
channels. in the triggering VGICs is represented by a change in transmembrane voltage or is
represented by a change in the chemical composition of the intra or extracellular
environment (ligand-gated ion channels (LGIC). Ion channels having the same selectivity are
often distinguished by their conductance (γ), which is the ratio between the current carried
(i) and the electromotive force (V). Under most physiological conditions, inflow currents (
cations influx the cell or by anions flowing into the extracellular space) cause membrane
depolarization, whilst outflow currents (cations exit the cytoplasm or by anions influx the
cell) make the membrane hyperpolarize.

The VGICs opening probability is membrane potential since the membrane plays the
role as the main regulator. Majority VGICs are activated or can be called opened by the
depolarization of membranes, though few of them are activated by membrane
hyperpolarization. But in some channels, besides those two states (open and close), there is
an additional state named inactivated state. This inactivation is produced by an inactivation
process, a closed state-like condition where ions are unable to flow past the channel pores.
But on the contrary, ion channels that are inactivated state will be unable to be reopened
only by depolarization, it needs to return to the closed state before the activation process
can proceed. In summary, the voltage dependence, inactivation and ion selectivity are the
main properties of voltage gated ion channels.

Drug-induced changes frequently refer to changes in the functional behavior of ion

channels indirectly.Biochemical and pharmacological modulation of specific ion channels is
essential for discovering the mechanisms of action of available drugs and for planning
innovative strategies aimed at ion channels. Some drugs must interact directly with certain
ion channels to exert a therapeutic effect. As targets Na+ channels (local anesthetics,
anticonvulsants, antiarrhythmics, diuretics). Ca+ channels (antihypertensives, antianginal
drugs, other antiarrhythmics). Other K+ channels (additional class of antiarrhythmics, oral
glucose-lowering drugs, vasodilators, and some anticonvulsants).

The voltage-gated sodium channel consists of a single polypeptide arranged into

several functional domains. Several isoforms are known, classified into nine distinct
subfamilies. They are major players in the generation of action potentials in excitable cells.
sodium channel-acting drugs are used in controlling cardiac arrhythmias, epileptic discharge,
and local anesthetics. Up to 10 distinct subfamilies of voltage-gated calcium channels have
been identified, differing in location, threshold of activation and inactivation rate. Drugs
acting on this channel are relevant for treatment of various cardiovascular diseases. The
most important drug classes acting on VGSCs are Local anesthetics (blocking VGSCs in
peripheral nerves), Anticonvulsant (blocking VGSCs in central neurons), Class I
antiarrhythmics (blocking cardiac VGSCs), andMuscle relaxants (blocking VGSCs in skeletal
muscle). VGSC is blockers in cardiovascular diseases since it can inhibit reentry arrhythmias,
reduce delayed afterdepolarization‐induced extrasystoles, and decrease AP duration and
prevent early afterdepolarizations (EADs).

Potassium channels vary in the molecular organization of their subunits and the
channel complex. Potassium channels can be activated by different stimuli including
voltage, Ca2+ and ATP. Drugs acting on potassium channels are used in a variety of ailments,
from hypertension to diabetes and to epilepsy. Drugs acting on membrane metabotropic
receptors, by interfering with intracellular or membrane-bound signaling pathways , can
indirectly modulate the function of ion channels, further expanding the pharmacological role
of this class of membrane proteins.

MEMBRANE TRANSPORTERS

Transmembrane transport may or may not be ATP dependent on . The

ATP-dependent transporter uses the energy provided by the hydrolysis of ATP to translocate
ions, drugs, and other substrates. They are divided into ATP‐binding cassette (ABC)
transporters, P transporters, and F and V transporters. ABC transporters restrain the energy
released by ATP hydrolysis that is used to transport various substances (lipids, small
molecules, large polypeptides, ions, and drugs) across membranes of the cell. P transporters
are primarily deputed to ion transport meanwhile F and V transporters are more complex
ATPases involved exclusively in proton transport. ATP-independent transporters use the
energy provided by counterion electrochemical gradients to translocate ions,
neurotransmitters and other substrates. It can be mediated by Solute Carrier transporters, a
super family that also consist of genes that encode for proteins mediating the so‐called
facilitated transport as well as includes the genes that encode for proteins mediating a
secondary active transport coupled to ion exchange. Diuretics, proton pump inhibitors, and
cardiac glycosides are the examples of drug classes that act on membrane transporters.
Cardiac glycosides inhibit Na + / K + -ATPase and interfere with intracellular concentrations
of Na + , K + and Ca 2 +, This results in a depolarizing and inotropic effect. Gastric proton
pump inhibitors have revolutionized gastric ulcer therapy. Some diuretics act on ion
transporters present in different segments of the nephrons. The pharmacological
importance in these membrane transporters lies in the fact that compounds capable of
modulating their activity can contribute to altering the pharmacokinetic and
pharmacodynamic properties of drugs.

NEUROTRANSMITTER TRANSPORTER

Transporters regulate the concentration of neurotransmitters in the synaptic cleft in

the central and peripheral nervous systems. Transmitter transport against the concentration
gradient is coupled with Na+ or H+ cotransport along its concentration gradient. Build upon
their subcellular distribution, structure molecularly, and pharmacological properties,
transporters can be splitted into three, namely Na+/K+ ‐dependent plasma membrane
transporters of GLU and aspartate (ASP), Na+ /Cl− ‐dependent plasma membrane
transporters of GABA and catecholamines, and H+ ‐dependent vesicle membrane
transporters of monoamines, ACh, and amino acids. Norepinephrine carriers can also absorb
dopamine, a precursor of norepinephrine. In brain areas, such as the prefrontal cortex,
where the density of noradrenergic terminals is high compared to dopaminergic, NET plays a
more important role than DAT in the elimination of dopamine from the extracellular
compartment. Catecholamine transport is an indirect target of cocaine and
sympathomimetics. Monoamine and serotonin transport are targets for drugs used to treat
depression. Membrane and vesicular transport of GABA is the target of several antiepileptic
drugs.