7 Ways You Inhibit Your GABA Receptor

The GABAergic system refers to the network of neurons that use gamma-aminobutyric acid (GABA) as their primary neurotransmitter. GABA is the main inhibitory neurotransmitter in the CNS or central nervous system. GABA synthesis begins with glutamate via the glutamate decarboxylase enzymes (GAD65 and GAD67). Once synthesized, GABA is stored in synaptic vesicles and released into the synaptic cleft upon the arrival of an action potential. GABA binds to three different receptors called GABA-A, GABA-B, and GABA-C. GABA-A and -C receptors are ionotropic, meaning that they function as ligand-gated channels. When GABA binds to these receptors, it allows the influx of chloride ions, leading to the hyperpolarization of neurons and decreased neuron excitability [1]. GABA-B receptors are metabotropic receptors that are coupled with G-proteins. They mediate longer-lasting inhibitory effects by influencing ion channels and second messenger systems [2].

GABA-A receptor structure

GABA-A receptors are ligand-gated ion channels, particularly the pentameric [16]. They are composed of five different proteins from a selection of 19 subunits: six α (α 1-6), three β (β 1-3), three γ (γ 1-3), three ρ (ρ 1-3), and one each of the δ, ε, π, and θ subunits [17]. Combinations of these 19 subunits produce numerous receptor isoforms, each with unique localization patterns and distinct physiological and pharmacological properties. However, the most common GABA-A receptor combination is composed of two α, two β, and one γ subunit arranged as γ-β-α-β-α around a central axis [18-20].

GABA-A receptors and allosteric modulators

GABA-A receptors are modulated by a variety of drugs [1]. Benzodiazepines, barbiturates, or neurosteroids, among others, can bind to GABA-A receptors. This pharmacological diversity is related to the presence of distinct binding sites on the structures of the receptor subunits [21-24]. Many of these drugs act as allosteric modulators. Their binding triggers a conformational change in another site of the GABA-A receptors. These changes can either promote or impede the open state of the pore [25,26]. Barbiturates, benzodiazepines, alcohol (ethanol), and anesthetic drugs are positive allosteric modulators that enhance the activation of GABA-A receptors. In contrast, bicuculline, picrotoxin, dehydroepiandrosterone sulfate (DHEAS), and beta-carbolines are negative allosteric modulators that diminish the activation of GABA-A receptors [27].

 

Negative allosteric modulators

DHEAS

DHEAS, a neurosteroid, is known to inhibit GABA responses, as measured by GABA-induced chloride influx in mammalian cultured cortical neurons [28]. While previous work proposed that DHEAS inhibits GABA-A receptors by enhancing the rate of entry into its desensitized state, a recent study shows that DHEAS interacts with GABA-A receptors to stabilize a novel nonconducting state [28,29].

Beta-carbolines

Beta-carbolines are inverse agonists of GABA-A receptors binding to the benzodiazepine site. At low concentrations, they reversibly decrease GABA-A currents. When methyl-6,7-dimethoxyl-4-ethyl-b-carboline-3-carboxylate (DMCM), a beta-carboline, is applied with GABA on spinal cord neurons in culture, GABA-A receptor openings decrease compared with GABA alone. DMCM reduces receptors' single openings and burst frequency [27]. Interestingly, at high concentrations, DMCM becomes a positive modulator, especially in the presence of flumazenil, and enhances GABA-elicited currents[30]

GABA-A receptor changes induced by chronic activation

Benzodiazepines

Chronic administration of benzodiazepines results in tolerance, limiting their efficacy. A study in rat cerebrocortical neurons showed that prolonged diazepam treatment induced uncoupling between the GABA and benzodiazepine sites. In other words, the ability of the benzodiazepine binding site to influence the GABA binding site is reduced or lost. Consequently, diazepam binding to GABA-A receptor no longer effectively increases the receptor's response to GABA, diminishing its therapeutic effect. Other studies have reported GABA-A receptor uncoupling triggered by benzodiazepines [32]. In addition, diazepam, via activation of L-type voltage-gated calcium channels, also produces selective transcriptional downregulation of the α1 subunit gene [33]. Internalization mechanisms of the receptors and changes in phosphorylation have also been observed [34].

Alcohol (ethanol)

Like benzodiazepines, ethanol enhances GABA activity at GABA-A receptors. A study in rats demonstrated that chronic ethanol exposure selectively induced the internalization of α1 subunit-containing GABA-A receptors in the cerebral cortex [35]. Chronic ethanol consumption also alters subunit gene expression as a compensatory mechanism. Thus, the expression of α1, α2, α3, and δ subunits is down-regulated, while the one of α4, β1, β2, β3, γ1, and γ2 subunits is up-regulated in the rodent cerebral cortex [36]. Uncoupling mechanisms and changes in phosphorylation have also been reported [37].

Caffeine

Caffeine induces various effects on the GABAergic system, including GABAergic receptors [38-42]. Exposure to caffeine has been shown to alter the function of GABA-A receptors, potentially affecting chloride transport [41] and influencing the availability of GABA/benzodiazepine receptor sites [42,43].

Indirect GABAergic modulation

Other compounds, such as opioids and cannabinoids, do not directly interact with GABA receptors but still reduce GABAergic signaling by acting on their respective receptors.

Opioids

Opioid receptors (mu, delta, and kappa), present across brain regions, play crucial roles in regulating the release of glutamate and GABA via presynaptic mechanisms, as well as in modulating neuronal excitability through postsynaptic mechanisms. There is considerable heterogeneity in the specific mechanisms by which opioid receptors regulate GABA release, even within the same brain region. At some synapses, this regulation involves the inhibition of calcium channels, while at others, it involves the activation of potassium channels [44]. For example, opioids, via binding presynaptic mu and delta opioid receptors of interneuronal terminals, decrease GABA release in the hippocampus, amygdala, and cortical areas [44-47].

Tetrahydrocannabinol (THC)

THC can inhibit GABA release via presynaptic cannabinoid receptor 1 without causing postsynaptic effects and without altering GABA-A receptors or GABA uptake in the hippocampus.[48,49].

Conclusion

In conclusion, various categories of molecules influence GABA-A receptors and modulate GABAergic signaling, playing a crucial role in maintaining the balance of neuronal activity in the central nervous system. A reduction in GABA-A receptor signaling can have profound physiological and neurological effects, such as heightened neuronal excitability, altered pain perception, mood changes, increased anxiety, and seizures.

 

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