Ligand-Gated Ion Channels Nu-643-01-19 Advanced Psychopharmacology Regis College Karen Watson Shantiah Norfleet Gwendolyn Molina Tasia Porter Topic Explain Ion channels as a target of pharmacological drug action Describe the essentials of ligand-gated ion channels Explore the structure and function of Ligand-Gated Ion Channels Elaborate on the Allosteric Modulation Survey possible states of Ligand-Gated Ion Channels Discuss the Agonist Spectrum Ligand- Gated Ion Ion channels are present upon the membranes of many types of cells in our bodies. These channels act to selectively control the ability of ions to move into and out of the cells (Stahl, 2013). These channels are important because without them ions would not be able to penetrate the cell membrane due to their charged nature. Two main classes of these are ligand-gated ion channels and voltage sensitive-ion channels (Stahl, 2013). This discussion will briefly focus upon what is known about ligand-gated ion channels and their roles in psychopharmacological drug action as discussed in Stahl (2013) Given the importance of ions and ion channels in the maintenance of cells and cellular functioning, there are multiple types of ion channels. 3 Ligand-Gated Ion Channels are Targets of Drug Actions A ligand is a chemical that binds to a receptor. Whenever a ligand binds to an appropriate receptor on the cell, it makes a change in the conformation of the receptor that causes the ion channel to open. Many neurotransmitters act as ligands on cell receptors, and many pharmaceutical compounds can similarly act as ligands on these same receptors. The actions of the ligand on the receptor cause changes downstream from the receptor’s signals as well, and this can change things like enzyme activity, receptor sensitivity, gene expression, and amplification of gene functions (Stahl, 2013). ​ Ion channels are present upon the membranes of many types of cells in our bodies. These channels act to selectively control the ability of ions to move into and out of the cells (Stahl, 2013). These channels are important because without them ions would not be able to penetrate the cell membrane due to their charged nature. Given the importance of ions and ion channels in the maintenance of cells and cellular functioning, there are multiple types of ion channels. Two main classes of these are ligand-gated ion channels and voltage sensitive-ion channels (Stahl, 2013). This discussion will briefly focus upon what is known about ligand-gated ion channels and their roles in psychopharmacological drug action as discussed in Stahl (2013) 5 Ligand-Gated Ion Other Possible States of Ligand-Gated Ion Channels Ion channels can be in the resting state, when they aren’t allowing more than a baseline flow of ions across them, in an open state when they are allowing ions to flow, and in a closed state, when they are fully closed and do not even allow baseline levels of ion tra ...

1. Ligand-Gated Ion Channels
Nu-643-01-19 Advanced Psychopharmacology
Regis College
Karen Watson
Shantiah Norfleet
Gwendolyn Molina
Tasia Porter
Topic
Explain Ion channels as a target of pharmacological drug action
Describe the essentials of ligand-gated ion channels
Explore the structure and function of Ligand-Gated Ion
Channels
Elaborate on the Allosteric Modulation
Survey possible states of Ligand-Gated Ion Channels
Discuss the Agonist Spectrum
Ligand- Gated Ion
Ion channels are present upon the membranes of many types of

2. cells in our bodies.
These channels act to selectively control the ability of ions to
move into and out of the cells (Stahl, 2013).
These channels are important because without them ions would
not be able to penetrate the cell membrane due to their charged
nature.
Two main classes of these are ligand-gated ion channels and
voltage sensitive-ion channels (Stahl, 2013).
This discussion will briefly focus upon what is known about
ligand-gated ion channels and their roles in
psychopharmacological drug action as discussed in Stahl (2013)
Given the importance of ions and ion channels in the
maintenance of cells and cellular functioning, there are multiple
types of ion channels.
3
Ligand-Gated Ion Channels are Targets of Drug Actions
A ligand is a chemical that binds to a receptor. Whenever a

3. ligand binds to an appropriate receptor on the cell, it makes a
change in the conformation of the receptor that causes the ion
channel to open.
Many neurotransmitters act as ligands on cell receptors, and
many pharmaceutical compounds can similarly act as ligands on
these same receptors.
The actions of the ligand on the receptor cause changes
downstream from the receptor’s signals as well, and this can
change things like enzyme activity, receptor sensitivity, gene
expression, and amplification of gene functions (Stahl, 2013).
Ion channels are present upon the membranes of many types of
cells in our bodies. These channels act to selectively control the
ability of ions to move into and out of the cells (Stahl, 2013).
These channels are important because without them ions would
not be able to penetrate the cell membrane due to their charged
nature. Given the importance of ions and ion channels in the
maintenance of cells and cellular functioning, there are multiple
types of ion channels. Two main classes of these are ligand-
gated ion channels and voltage sensitive-ion channels (Stahl,
2013). This discussion will briefly focus upon what is known
about ligand-gated ion channels and their roles in
psychopharmacological drug action as discussed in Stahl (2013)
5
Ligand-Gated Ion
Other Possible States of Ligand-Gated Ion Channels

4. Ion channels can be in the resting state, when they aren’t
allowing more than a baseline flow of ions across them, in an
open state when they are allowing ions to flow, and in a closed
state, when they are fully closed and do not even allow baseline
levels of ion transfer (Stahl, 2013).
Another possible state of the channel is inactivation, which
comes about by the action of an inverse agonist which over time
stabilizes the ion channel so that it can be quickly activated by
an antagonist.
Desensitization is another state that occurs when the receptor
has been exposed to agonists for a prolonged period and the
receptor stops responding to the agonist (Stahl, 2013).
Modulation in Action (I.e.-agonist spectrum, PAM, NAMS, etc.)
According to Stahl (2013), there are three ranges of the agonist
spectrum; agonists, antagonists, and partial agonists (pg. 1666).
Full agonists change the formation of the receptor to open the
ion channel to its maximum frequency and amount, then causing
the highest availability of “downstream signal transduction
possible to be intermediated by the binding site (pg. 1666).
Partial agonists are noted to increase the degree and frequency
of ion-channel opening as compared to the resting state but not
as much as the full agonists, and antagonists can block anything
in the agonist spectrum and stabilizes the receptor in the resting
state, returning the ion channel to the resting state (pg. 1677).
Partial agonists can both boost deficient neurotransmitter
activity yet block excessive neurotransmitter activity, acting as
a stabilizer (pg. 1734). An inverse agonist is noted to perform
opposite of an agonist, decreasing signal transduction if an
agonist increases it, as well as stabilizing an inactivated state,
causing conformational change that closes the ion channel (pg.
1770-1771). Only after this process the ion channel them opens
to an even greater frequency, with the support of a second

5. receptor site, such as a positive allosteric modulator.
Allosteric modulation occurs when molecules other than
neurotransmitters are able to bind the receptor at a different site
than the customary ligand.
Positive allosteric modulators (PAMs) are able to enhance the
effects of the ligand (neurotransmitter), while negative
allosteric modulators (NAMs) are able to block the actions of
the ligands.
As long as the neurotransmitter is not binding to the receptor,
the PAM and NAM will have no action – these only cause
conformation changes in the channel when the ligand is also
present (Stahl, 2013).
8
Modulation in Action (I.e.-agonist spectrum, PAM, NAMS, etc.)
cont’
The two forms of allosteric modulators, positive allosteric
modulators (PAM) and negative allosteric modulators (NAM)
both enhance and block the actions of neurotransmitters yet
have no activity on their own (pg. 1827). PAM causes
conformational changes in the ligand-gated ion channel in the
presence of the neurotransmitter when an agonist is also bound,
which then causes the channel to open more frequently,
allowing more ions into the cell (pg. 1843).
When a NAM causes changes in the ligand-gated ion channel,
its purpose is to act negatively in blocking or reducing the
actions that normally occur when the neurotransmitter acts
alone (pg. 1843).

6. How is it relative to psychopharmacology?
Regulates calcium, chloride and potassium
Key targets to many psychotropic medications
Key regulators of of chemical neurotransmission
Facilitate the flow of ions across the cell membrane
Allows translation of the message
As mention by Alexander, et al. (2017) said ion channels are
pore-forming protein complexes that facilitate the flow of ions
across the hydrophobic core of cell membranes. They are
present in the plasma membrane and membranes of intracellular
organelles of all cells, performing essential physiological
functions including establishing and shaping the electrical
signals which underlie muscle contraction/relaxation and
neuronal signal transmission, neurotransmitter release,
cognition, hormone secretion, sensory transduction and
maintaining electrolyte balance and blood pressure.
10
Ligand-gated ion channels
Ligand-gated ion channels is relative to psychopharmacology
because most of the medications utilized in mental health will
act upon the necessary channels to cause a change within the
cell.
The ligand-gated ions are gate-keepers are receptors that help to
regulate what ions go into the cell and what ions stay out of the
cell.

7. The Structure and Function of Ligand-Gated Ion Channels
Because Ligand-gated ion channels have unique structures and
subtypes, a prescriber has the ability to choose a drug that will
target the right channels.
What drug class would be effective in helping reduce depression
as well, as enhance the quality of sleep?
For example, the psychiatric mental health practitioner has the
ability to look at the client, assess his or her symptoms, see that
they are having depression and difficulty sleeping. The
practitioner may use a symptom algorithm.
Mirtazapine, a tetracyclic antidepressant, that works by
inhibiting the reuptake of neurotransmitter serotonin to elevate
the mood. This medication is a 5HT3 ligand-gated ion-channel
receptor, an antagonist that allows for a resting state, and some
ions get throught the channel to cause a reaction. The overall
effect for the patient is an effective night sleep and improved
depressive symptoms.
13
References
Alexander, S. P., Peters, J. A., Kelly, E., Marrion, N. V.,
Faccenda, E., Harding, S. D., … CGTP Collaborators (2017).
THE CONCISE GUIDE TO PHARMACOLOGY 2017/18:
Ligand-gated ion channels. British journal of pharmacology,
174 Suppl 1(Suppl Suppl 1), S130–S159.

8. doi:10.1111/bph.13879.
Betry, C., Etievant, A., Oosterhof, C., Ebert, B., Sanchez, C., &
Haddjeri, N. (2011).Role of 5-HT3 Receptors in the
Antidepressant Response, Pharmaceuticals (Base), 4(4), 603-
629. Retrieved from:
https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4055881/
Drugs.com (2019). Tetracyclic antidepressants. Retrieved from:
https://www.drugs.com/drug-class/tetracyclic-
antidepressants.html
LibreTexts. (2019, June23). Ligand-gated Ion Channel
Receptors.
Stahl, S. (2013). Essential psychopharmacology: Neuroscientific
Basis and Practical Applications (4th ed.). Cambridge, England:
Cambridge University Press.
Wikipedia. (2007, April 11). Ligand-gated ion channel.
Voltage-sensitive Ion Channels As Targets of Drug Action
What are Ion Channels?
What? Pore-forming protein complexes that facilitate the flow
of ions across the hydrophobic core of cell membranes
WHERE? Plasma membrane and membranes of intracellular
organelles of all cells
WHY? Involved in muscle contraction/relaxation, neuronal
signal transmission, neurotransmitter release, cognition,
hormone secretion, sensory transduction, electrolyte balance,
and blood pressure
Basics of How they work
Gates are opened or closed depending on ionic charge or voltage
potential
The opening of the gates change the polarity of the cell
membrane

9. A series of these changes move along the neuron
There are 4 major ions involved. Sodium, Calcium, Potassium
& Chloride. Most Na+, K+, Ca2+ and some Cl- channels are
gated by voltage, whereas others are relatively voltage-
insensitive and are gated by second messengers and other
intracellular and/or extracellular mediators (Pharmacology
Education Project, 2019)
Ion channels are classified by gating the stimulus that opens and
closes the channel, be it chemical or mechanical stimuli, and are
regulated by the ionic charge or voltage potential across the
membrane in which they reside (Pharmacology Education
Project, 2019)
These channels exist in 3 states: open, closed/resting, and
inactive state . Certain ion channels undergo conformational
change on binding with molecules and can thus switch between
the three states within milliseconds (Jacob, 2017). Critical
aspects of nerve conduction, action potentials, and
neurotransmitter release are all mediated by ion channels that
are "voltage sensitive" or "voltage gated" ion channels (Stahl,
2013)
Our next slide will show a video of these gates in action.
An electrical impulse in a neuron, also known as the action
potential, is triggered by summation of the various
neurochemical and electrical events of neurotransmission .
Voltage sensitive ion channels are opened and closed by the
voltage charge across the membrane (Stahl, 2013)
Voltage Gated Ion Channels are rapid, exhibit highly selective
permeability, and are responsive to changes in the local
electrical membrane potential which are critical for the function
of excitable cells, such as neurons and muscle cell and are
subject to conformational change based on changing membrane
potential (Jacob 2017).

10. Electrically, the first phase of the action potential is sodium
rushing "downhill" into the sodium-deficient, negatively
charged internal milieu of the neuron made possible when
voltage-gated sodium channels open the gates and let the
sodium in (Stahl, 2013).
A few milliseconds later, the calcium channels get the same
idea, with their voltage-gated ion channels opened by the
change in voltage potential caused by the sodium rushing in
(Stahl, 2013).
Voltage-gated ion channels hare not as simple as just a pore in
the cell membrane. These channels are long strings of amino
acid that contain 4 subunits. Each subunit has six
transmembrane segment. Transmembrane #4 acts like a volt
meter (it’s the one in the picture with the lightning bolt) when it
detects a change it alerts the rest of the protein. The final result
is that the ion channel either opens or closes. Each subunit of a
voltage sensitive ion channel has an extracellular amino acid
loop between transmembrane segments 5 and 6. This serves as
an “ionic filter” (think of a colander which allows only certain
ions to filter through) (Stahls, 2013)
· Sodium is kept out of the neuron when the channel is
closed/inactivated and the direction of sodium flow is into the
neuron when the channel is open/activated
· Voltage-sensitive sodium channels may have regulatory
proteins, known as beta units, located in the transmembrane
area and flanking the alpha pore-forming unit.
· Beta subunits may indirectly influence the opening and closing
of the channel.
· Various sodium channels may be the sites of action of several
anticonvulsants, some of which have mood stabilizing and pain
reducing properties.
Voltage Sensitive calcium Channels

11. Amino acids connecting the second and third subunits of the
channel work as a “snare” to hook up with the synaptic
vesicles and regulate the release of neurotransmitter into the
synapse during synaptic neurotransmission (Stahl, 2013).
• The direction of ion flow is from outside the cell to inside
the cell when the channel opens to allow ion flow to occur
(Stahl, 2013).
• Downstream of the depolarization induced by calcium
activates calcium-dependent non-specific cationic channels
which maintains the neuron in a depolarized state
(Altunrende et al., 2018).
· Approximately 10% of psychotropic medications have voltage
gated ion channels as their mode of action
· Various voltage sensitive sodium channels may be the sites of
action of several anticonvulsants, some of which have mood
stabilizing and pain reducing properties. These would
gabapentin, pregabalin, lamotrigine, carbamazepine,
oxcarbazepine, and zonisamide.
· The specific subtypes of voltage sensitive calcium channels
of most interest to psychopharmacology are those that are
presynaptic, that regulate neurotransmitter release, and that are
targeted by certain psychotropic drugs
Together, ligand-gated and voltage-sensitive ion channels work
cooperatively during neurotransmission communicating with
between a mix of electrical and chemical messages made
possible by ion channels
Week 3 :Reply Posts Group Presentation on Stahl Readings
View your peers’ group presentation posts and respond to two
groups. In your response post answer the following questions:
· What did you find interesting about the presentation?
· What did you learn from this that you may not have during the

12. reading?
· Are there any aspects of this topic that are still unclear? What
do you plan to do to fill in these gaps in knowledge?
Please refer to the Grading Rubric for details on how this
activity will be graded.
The described expectations meet the passing level of 80%.
Students are directed to review the Discussion Grading Rubric
for criteria which exceed expectations.