User:JdanR/Agonist

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Mechanism of Action

As mentioned above, agonists have the potential to bind in different locations and in different ways depending on the type of agonist and the type of receptor.^[1] Typically, the process of binding is unique to the receptor-agonist relationship, but the binding induces a conformational change and activates the receptor.^[1]^[2] Two examples that demonstrate this process are the muscarinic acetylcholine receptor and NMDA receptor and their respective agonists.

For the muscarinic acetylcholine receptor, which is a G protein-coupled receptor^[2](GPCR), the endogenous agonist is acetylcholine. The binding of this neurotransmitter causes the conformational changes that propagate a signal into the cell.^[2] The conformational changes are the primary effect of the agonist, and are related to the agonist's binding affinity and agonist efficacy.^[1]^[3] Other agonists that bind to this receptor will fall under one of the different categories of agonist mentioned above based on their specific binding affinity and efficacy.

The NMDA receptor is an example of an alternate mechanism of action, as the NMDA receptor requires co-agonists for activation. Rather than simply requiring a single specific agonist, the NMDA receptor requires both the endogenous agonists, N-methyl-D-aspartate (NMDA) and glycine.^[4] These co-agonists are both required to induce the conformational change needed for the NMDA receptor to allow flow through the ion channel, in this case calcium.^[4] An important aspect demonstrated by the NMDA receptor is that the mechanism or response of agonists can be blocked by a variety of chemical and biological factors^[4]. NMDA receptors specifically are often blocked by a magnesium ion unless the cell is also experiencing depolarization.^[4]

These differences show that agonists have unique mechanisms of action depending on the receptor activated and the response needed.^[1]^[2] The goal and process remains generally consistent however, and the primary mechanism of action requires binding of the agonist and the subsequent changes in conformation to cause the desired response at the receptor.^[1]^[3] This response as discussed above can vary from allowing flow of ions to activating a GPCR and transmitting a signal into the cell.^[1]^[2]

^ ^a ^b ^c ^d ^e ^f Colquhoun, David (2006). "Agonist-activated ion channels". British Journal of Pharmacology. 147 (S1): S17–S26. doi:10.1038/sj.bjp.0706502. ISSN 1476-5381. PMC 1760748. PMID 16402101.{{cite journal}}: CS1 maint: PMC format (link)
^ ^a ^b ^c ^d ^e Kruse, Andrew C.; Ring, Aaron M.; Manglik, Aashish; Hu, Jianxin; Hu, Kelly; Eitel, Katrin; Hübner, Harald; Pardon, Els; Valant, Celine; Sexton, Patrick M.; Christopoulos, Arthur (2013-12-05). "Activation and allosteric modulation of a muscarinic acetylcholine receptor". Nature. 504 (7478): 101–106. doi:10.1038/nature12735. ISSN 0028-0836. PMC 4020789. PMID 24256733.
^ ^a ^b Strange, P G (2008). "Agonist binding, agonist affinity and agonist efficacy at G protein-coupled receptors". British Journal of Pharmacology. 153 (7): 1353–1363. doi:10.1038/sj.bjp.0707672. ISSN 0007-1188. PMC 2437915. PMID 18223670.
^ ^a ^b ^c ^d Zhu, Shujia; Stein, Richard A.; Yoshioka, Craig; Lee, Chia-Hsueh; Goehring, April; Mchaourab, Hassane S.; Gouaux, Eric (2016-04-21). "Mechanism of NMDA receptor inhibition and activation". Cell. 165 (3): 704–714. doi:10.1016/j.cell.2016.03.028. ISSN 0092-8674. PMC 4914038. PMID 27062927.

References

Colquhoun, D. (2009). Agonist-activated ion channels. British Journal of Pharmacology, 147(S1). https://doi.org/10.1038/sj.bjp.0706502

Kruse, A. C., Ring, A. M., Manglik, A., Hu, J., Hu, K., Eitel, K., Hübner, H., Pardon, E., Valant, C., Sexton, P. M., Christopoulos, A., Felder, C. C., Gmeiner, P., Steyaert, J., Weis, W. I., Garcia, K. C., Wess, J., & Kobilka, B. K. (2013). Activation and allosteric modulation of a muscarinic acetylcholine receptor. Nature, 504(7478), 101–106. https://doi.org/10.1038/nature12735

Strange P. G. (2008). Agonist binding, agonist affinity and agonist efficacy at G protein-coupled receptors. British journal of pharmacology, 153(7), 1353–1363. https://doi.org/10.1038/sj.bjp.0707672

Zhu, S., Stein, R. A., Yoshioka, C., Lee, C. H., Goehring, A., Mchaourab, H. S., & Gouaux, E. (2016). Mechanism of NMDA Receptor Inhibition and Activation. Cell, 165(3), 704–714. https://doi.org/10.1016/j.cell.2016.03.028

[:0-1] ^ ^a ^b ^c ^d ^e ^f Colquhoun, David (2006). "Agonist-activated ion channels". British Journal of Pharmacology. 147 (S1): S17–S26. doi:10.1038/sj.bjp.0706502. ISSN 1476-5381. PMC 1760748. PMID 16402101.{{cite journal}}: CS1 maint: PMC format (link)

[:1-2] Kruse, Andrew C.; Ring, Aaron M.; Manglik, Aashish; Hu, Jianxin; Hu, Kelly; Eitel, Katrin; Hübner, Harald; Pardon, Els; Valant, Celine; Sexton, Patrick M.; Christopoulos, Arthur (2013-12-05). "Activation and allosteric modulation of a muscarinic acetylcholine receptor". Nature. 504 (7478): 101–106. doi:10.1038/nature12735. ISSN 0028-0836. PMC 4020789. PMID 24256733.

[:2-3] Strange, P G (2008). "Agonist binding, agonist affinity and agonist efficacy at G protein-coupled receptors". British Journal of Pharmacology. 153 (7): 1353–1363. doi:10.1038/sj.bjp.0707672. ISSN 0007-1188. PMC 2437915. PMID 18223670.

[:3-4] Zhu, Shujia; Stein, Richard A.; Yoshioka, Craig; Lee, Chia-Hsueh; Goehring, April; Mchaourab, Hassane S.; Gouaux, Eric (2016-04-21). "Mechanism of NMDA receptor inhibition and activation". Cell. 165 (3): 704–714. doi:10.1016/j.cell.2016.03.028. ISSN 0092-8674. PMC 4914038. PMID 27062927.

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