Group Presentation on Stahl Readings part I
rmellecutie
ligandgroupproject.pptx
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.
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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)
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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 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 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).
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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).
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.
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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.
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.
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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. 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.
