Pharmacology of

Cell Excitation

Mayurakkhi Bhatia
College of Pharmacy
Long Island University
 • Channels are controlled by intracellular
ligands.
• Cyclic Nucleoside-Gated (CNG) channels.
• Inward rectifier potassium (Kir ) channels.
• Transient Receptor Potential (TRP)
Contents channels.
• Voltage-gated channels of nerve cells as
drug targets.
• Sodium channel blockers in local
anesthesia.
• Voltage-gated channels and epilepsy.
 • Ligand-gated channels can be
classified based on where the ligand
binding site is located.
• Extracellular-Outside the cell
Channels • Intracellular-Within the cell
Controlled • Extracellularly binding ligands
by includes neurotransmitters ( ex.
Ionotropic receptors).
Intracellular • Intracellular ligands maybe
Ligands secondary messengers that relay
extracellular signals (ex. Calcium
play a role in calcium activated
potassium channels).
Cyclic
Nucleoside-
Gated (CNG)
Channels
 It includes 4 subunits that each
contain 6 transmembrane helices.
 Each subunit contains one cyclic
nucleotide binding site.
 Binding of cAMP or cGMP opens
the channel for Na+, K+, Ca2+

Figure1: Topology of a cyclic nucleoside-gated channel subunit.

Reference : Wong, Ching-On and Xiaoqiang Yao. “Cyclic nucleotide-gated channels: a familiar channel family with a new function?” Future
cardiology 4 5 (2008): 505-15 .
 • Cyclic nucleotide-gated (CNG) channels are ion
channels which are activated by the binding of

Cyclic cGMP or cAMP.

• The channels are important cellular switches

Nucleosid which transduce changes in intracellular

concentrations of cyclic nucleotides into changes
of the membrane potential and the Ca2+
e-Gated concentration.
• Some CNG channels are controlled both by the
(CNG) membrane potential and by cyclic nucleotide
binding, thus defying the distinction between

Channels ligand-gated and voltage-gated channels.

• Such hyperpolarization-activated CNG channels,
or HCN channels for short, participate in the
generation of the rhythm in cardiac pacemaker
cells. Mutations affecting these channels can
cause cardiac arrhythmias.
 Inward rectifier
potassium (Kir) Channels
• Kir channels are also tetrameric in nature but
have a simpler structure than the voltage-
gated channels.
• 2 transmembrane helices in every subunit.
• When open, Kir channels hyperpolarize the cell.
• The name of this family of channels refers to
the fact that they conduct K+ ions more readily
into the cell than out of it.
• This is brought about by intracellular ions such
as Mg2+ and spermidine, which enter and plug
the channel lumen from inside when the
membrane potential is reversed.
Figure 2: crystal structure of an inward rectifier
potassium channel
Inward rectifier potassium (Kir)
Channels
• One notable group in this family are the G protein-coupled inward
rectifiers, or GIRK channels, which are activated by the βγ dimers of
some G proteins.
• Another important Kir channel is the KATP channel: It is associated with
the sulfonylurea receptor, which can bind two molecules of ATP and
then proceeds to close the KATP channel.
• In the β cells of the pancreatic islets, the sulfonylurea receptor is
involved in the control of insulin release.
• In muscle cells, the KATP channel appears to serve a protective function
—an exhausted cell that is running low on ATP will open the KATP
channels. This will hyperpolarize the membrane and cause the cell to
sit out some rounds of excitation in order to catch its breath.
Transient receptor potential (TRP)
Channels
 TRP channels are cation channels that
can be activated by very diverse
stimuli, mechanical force, heat, changes
in pH, intracellular and extracellular
ligands.
 TRPV1 is activated by heat and
capsaicin.
 TRP channels are important in the
perception of pain and sensory
qualities.
 TRP channel function most conductivity
for Ca2+
 Mechanosensitive TRP channel in skin,
hair cells.
 Ex: Experimental agonist of TRP4 Figure 3:Schematic representation of the shared structure of TRP
channels.
reduces blood pressure in animal, Reference: Vanneste, M., Segal, A., Voets, T. et al. Transient receptor potential channels
in sensory mechanisms of the lower urinary tract. Nat Rev Urol 18, 139–159 (2021).
mediated by influx of calcium and https://doi.org/10.1038/s41585-021-00428-6

activation of nitric oxide synthase.

 • Voltage-gated channels in nerve cells,
Voltage- particularly Na+ channels (NaV), are a
significant drug target due to their
Gated crucial role in generating and
propagating electrical signals (action
Channel of potentials) in neurons.
Nerve Cells • This makes them potential
therapeutic targets for conditions like
as Drug epilepsy, chronic pain, cardiac
arrhythmias, and muscle disorders.
Targets • This is possible by modulating their
activity through drugs that can block
or modulate their function.
Sodium Channel Blockers in Local
Anesthesia
 Blocking voltage –gated channels
suppresses the propagation of an action
potential.
 Systemic inhibition of Nav channels
paralyzes all nervous activity ( ex.
Tetrodotoxin)
 Batrachotoxin interacts with the channel
from within lipid bilayer and activates it.
 Mexiletine is metabolically stable analog
of lidocaine, used in cardiac arrhythmia
like quinidine.
 Phenytoin and Carbamazepine used to
Fig 4: Drugs and poisons that act on
Nav channels treat epilepsy and neurological
disorders.
 Sodium Channel Blockers in Local
Anesthesia
 The first Na channel-blocking drug to
V
be used for local anesthesia was
cocaine.
 Cocaine has been superseded as a local
anesthetic by structurally similar
compounds such as lidocaine.
 Local anesthetics affect sensory and
motor nerve fibers alike, which causes
the unpleasant facial paralysis that
accompanies anesthesia in dental
procedures.
 The channel block caused by lidocaine Figure 5: Fast and Slow blocks of Nav Channels
can be observed with single channel Fast block occurs when a drug reversibly binds
molecules. within the channel lumen and obstructs it. Slow
 The drug reduces the conductivity of block is observed when a drug binds to the
the open state, which is referred to as a inactivated state of the channel and delays its
fast block. In addition, it also slows reactivation
down the reactivation of the channel,
which is observed as a slow block.
 Sodium Channel Blockers in Local
Anesthesia
 Two types of blocks can be assigned to
separate moieties of the lidocaine
molecule.
 The block by lidocaine is use-dependent,
which means that the channels must be in
the open state before the drug can access
its binding site.
 Diethylamine binds and dissociates faster
than can be resolved by the instrument,
resulting in an apparent decrease in the
conductance of the open state.
 The extent of this decrease depends on
the membrane potential.
 Phenol causes extended intervals of
Figure 6: Structures of the sodium channel blocker
channel inactivity but does not change lidocaine, and of diethylamine and phenol, which
the conductivity of the open state. resemble two different moieties of the lidocaine
molecule. NaV channel conductance in the presence of
diethylamine. NaV channel conductance in the presence
of phenol.
Voltage-  Epilepsy has many variations, but a common motif is a

Gated pathological increase in the spontaneous activity and

excitability of groups of neurons in the brain.

Channels  Several forms of epilepsy can be attributed to mutant

ion channels.

and Epilepsy
 Pharmacological modulation of ion channels is widely
used in these cases, as well as in other forms of
epilepsy.
Voltage-Gated Channels and
Epilepsy
 NaV inhibitors used in the treatment of epilepsy are phenytoin and carbamazepine
 Unlike local anesthetics, they only cause slow channel block, in which they delay channel
reactivation.
 While the activity of most nerve cells depends on upstream input, some groups of nerve cells in the
brain generate intrinsic, spontaneous activity. This occurs in a manner like that of the pacemaker cells
in the heart and involves two different types of CaV channels, the T-type and the L-type channels.
 Mutations in T-type channel genes can cause a specific form of epilepsy known as generalized
absences. This condition is treated with ethosuximide, which inhibits T-type channels.
 In contrast to NaV and CaV channels, KV channels mediate membrane hyperpolarization, so that drugs
that promote the open state of these channels will reduce excitability.
 This therapeutic approach has only recently been put into practice. The drug retigabine promotes
opening of KCNQ or type 7 KV channels, which occur in the CNS and is currently in clinical trials.
References
TEXTBOOK OF BIOCHEMICAL
PHARMACOLOGY
-–M PALMER ( 2012 EDITION )
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