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Kava Fact of the Day Kavain acts as a positive allosteric modulator (PAM)

The Kap'n

The Groggy Kaptain (40g)
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Kavain as a Positive Allosteric Modulator

Today we’re going to return to one of our old topics to fill in some gaps. GABA-A. In the past I’ve described kavalactone’s binding ability to GABA as “enhancing” natural GABA to bind to its receptor. After further research, while accurate in simple terms, it is not the more complete picture. Kavalactones do enhance binding of GABA to the GABA-A receptor, and they do it in a familiar process. Also to address some misconceptions, kavain DOES likely bind at GABA-A, but not the way we observe for other compounds.

GABAA_receptor_binding_sites.jpg

TeamDolphins, GABAA receptor binding sites, 8 November, 2013, Digital JPG, 651x415 (https://commons.wikimedia.org/wiki/File:GABAA_receptor_binding_sites.jpg)​

We’ll need to define a few words here.

Orthosteric ligand (drug): This is a chemical that interacts with the same binding site as the natural endogenous chemicals found in our body (Jakubík et al. 2019). In this instance the natural chemical would be the neurotransmitter, GABA.

Allosteric ligand (drug, also known as a modulator): This is a chemical that works by modifying how the receptor behaves when it has been bound to an orthosteric ligand. The allosteric binding sites are distinctly separate from the site of the main transmitter, GABA’s binding site.

Positive allosteric modulator (PAM): a modulating chemical that binds to an allosteric site and increases the affinity or the efficacy of an agonist for that receptor (Kenakin 2017). Again, in this instance GABA will be the agonist that is being affected when it binds to the GABA-A receptor.

The positive allosteric modulator in this instance will be kava. Other examples of PAMs are drugs like alprazolam (xanax). Xanax binds to the benzodiazepine allosteric site on the GABA receptor and influences the receptor to allow the channel in the center to be open for longer periods of time, or more frequently. Kava extracts and pure kavalactones have been shown to enhance the effect when a natural neurotransmitter binds to that site similarly, but not identically to alprazolam, as kavalactones have not been shown to bind at the benzodiazepine site.

In 2016 a study was completed on the effects of kavain at various GABA-A subunit receptor sites (areas where allosteric chemicals bind). Kavain was found to positively modulate all receptors, regardless of subunit composition. It highly infers the probable existence of multiple binding sites in vivo for Kavain acting as a PAM. Of these sites the benzodiazepine site was ruled out completely by using the chemical Flumazenil, a blocker of benzo effects, while kavain still exerted its effects (Chua et al. 2016).

So to sum up, kavain acts on GABA-A receptors through the mechanism of Positive Allosteric Modulation. We’re still not completely sure which exact site on the GABA-A receptor subunits that Kavain binds to, but researchers are reasonably sure these sites exist. These are certainly novel sites, as withdrawal and tolerance are not seen like they are with common GABAergic active compounds. I feel like this gives a little more clarity than simply saying kavain “enhances'' GABA.


Chua, Han Chow, Emilie T. H. Christensen, Kirsten Hoestgaard-Jensen, Leonny Y. Hartiadi, Iqbal Ramzan, Anders A. Jensen, Nathan L. Absalom, and Mary Chebib. 2016. “Kavain, the Major Constituent of the Anxiolytic Kava Extract, Potentiates GABAA Receptors: Functional Characteristics and Molecular Mechanism.” PloS One 11 (6): e0157700.

Jakubík, Jan, Alena Randáková, Esam E. El-Fakahany, and Vladimír Doležal. 2019. “Analysis of Equilibrium Binding of an Orthosteric Tracer and Two Allosteric Modulators.” PloS One 14 (3): e0214255.

Kenakin, Terry P. 2017. “Chapter 5 - Allosteric Drug Effects.” In Pharmacology in Drug Discovery and Development (Second Edition), edited by Terry P. Kenakin, 101–29. Academic Press.
 
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