Disclaimer: This article is for popular science purposes only and does not constitute medical advice.

In the previous issue, we explored the discovery and sources of GABA. In this issue, we will delve into how GABA exerts its effects through three types of specific receptors, helping readers gain a more scientific understanding of this important neurotransmitter.

GABA-A Receptors (Non-ρ Subtypes): Ionotropic Receptors and Rapid Inhibitory Effects

GABA-A receptors are ligand-gated ion channels (i.e., channel proteins directly controlled by signaling molecules), composed of five subunits assembled into a pentameric structure. Upon binding to GABA-A receptors, GABA triggers the opening of chloride ion channels, leading to chloride ion influx and postsynaptic membrane hyperpolarization, thereby inhibiting neuronal firing^[1][2].

Many sedative-hypnotic drugs (e.g., benzodiazepines) and antiepileptic drugs (e.g., barbiturates) target GABA-A receptors. They amplify GABA’s inhibitory effects by enhancing GABA-receptor binding or prolonging the opening duration of chloride ion channels. Thus, GABA-A receptors can be regarded as the "switch" for rapid inhibition in the nervous system and a key target for numerous sedative drugs.

GABA-B Receptors: Metabotropic Receptors and Slow Regulatory Effects

GABA-B receptors are G protein-coupled receptors (GPCRs) that function by regulating other ion channels and intracellular signaling pathways. Consequently, their effects are slower to initiate but longer-lasting.

On the presynaptic membrane, activation of GABA-B receptors inhibits calcium ion influx and reduces neurotransmitter release, forming a crucial "presynaptic inhibition". On the postsynaptic membrane, their activation promotes potassium ion efflux, causing hyperpolarization of the neuronal membrane and generating slow, sustained "tonic inhibition".

This slow regulation is essential for maintaining neural network stability, adjusting neuronal excitability thresholds, and participating in advanced cognitive functions such as learning and memory^[2]. In essence, GABA-B receptors act as the "stabilizer" and "tuner" of neural networks.

GABA-Aρ Subtypes: Scientific Renaming and Roles in the Visual Pathway

In 2015, the International Union of Basic and Clinical Pharmacology (IUPHAR) reclassified the previously independently named "GABA-C receptors" into the GABA-A receptor ρ subunit family, i.e., homopentameric ion channels composed of ρ1, ρ2, or ρ3 subunits.

Studies have shown that compared with GABA-A receptors, receptors formed by ρ subunits have higher affinity for GABA and slower current decay, enabling them to mediate sustained and stable inhibitory signals. In the visual pathway, GABA-Aρ receptors are involved in regulating signal transmission between neurons, and are crucial for visual information integration, contrast sensitivity, and precise signal transduction^[3][4].

Beyond the retina, GABA-Aρ receptors have also been detected in brain regions such as the hippocampus and amygdala, but their physiological significance in regulating emotion and memory requires further research. It is evident that GABA-Aρ receptors play a role in the precise regulation of information processing such as vision.

Summary and Preview of the Next Issue

The mechanisms of the three receptor types mentioned above all occur within the central nervous system (CNS). Notably, for exogenous GABA administered orally to exert similar physiological effects, it must first cross biological barriers such as the blood-brain barrier (BBB) to bind to central GABA receptors. This critical link has sparked extensive discussions in the academic community. In the next issue, we will explore: Decoding Oral GABA: Academically Recognized Hypotheses on Its Mechanisms of Action.

参考文献

[1]Mohamad F H, Mohamad Jamali M A, Che Has A T. Structure-function Studies of GABA (A) Receptors and Related computer-aided Studies [J]. Journal of Molecular Neuroscience, 2023, 73(9–10): 804–817.

[2]周洪莉,张祚,周吉银.GABA能神经系统与学习记忆的研究进展[J].国际精神病学杂志, 2019, 46(6):4.

[3]Naffaa M M, Hung S, Chebib M, et al. GABA‐ρ receptors: Distinctive functions and molecular Pharmacology [J]. British Journal of Pharmacology, 2017, 174(13): 1881–1894.

[4]Calero C I, Vickers E, Moraga Cid G, et al. Allosteric Modulation of Retinal GABA Receptors by Ascorbic Acid [J]. Journal of Neuroscience, 2011, 31(26): 9672–9682.