GABAB Receptor: Structure, Biological Functions, and Therapy for Diseases

Abstract

Gamma-aminobutyric acid (GABA) B receptors (GABA_BRs) that acts slowly and maintains the inhibitory tone are versatile regulators in the complex nervous behaviors and their involvement in various neuropsychiatric disorders, such as anxiety, epilepsy, pain, drug addiction, and Alzheimer's disease. Additional study advances have implied the crucial roles of GABA_BRs in regulating feeding-related behaviors, yet their therapeutic potential in addressing the neuropsychiatric disorders, binge eating, and feeding-related disorders remains underutilized. This general review summarized the physiological structure and functions of GABA_BR, explored the regulation in various psychiatric disorders, feeding behaviors, binge eating, and metabolism disorders, and fully discussed the potential of targeting GABA_BRs and its regulator-binding sites for the treatment of different psychiatric disorders, binge eating and even obesity. While agonists that directly bind to GABA_BR1 have some negative side effects, positive allosteric modulators (PAMs) that bind to GABA_BR2 demonstrate excellent therapeutic efficacy and tolerability and have better safety and therapeutic indexes. Moreover, phosphorylation sites of downstream GABA_BRs regulators may be novel therapeutic targets for psychiatric disorders, binge eating, and obesity. Further studies, clinical trials in particular, will be essential for confirming the therapeutic value of PAMs and other agents targeting the GABA_BR pathways in a clinical setting.

Keywords: GABAB receptors; allosteric modulator; binge eating; metabolism disorders; molecular signaling; psychiatric disorders.

FIGURE 1

Structure, physiological functions, central distribution, and models of GABA_BR heterodimers and their potential role in mental disorders. Maps (A) and models (B) of four different conformations of GABA_BRs, including active and inactive states and two intermediate conformations. The numbers in parentheses indicate the estimated resolution of the cryo‐EM maps. GB1 and GB2 are blue and yellow, respectively. The agonist (SKF97541)‐ and PAM (GS39783)‐bound state is the active state. (C) Possible sites of action of presynaptic and postsynaptic GABA_BRs. (D) The distribution of GABA_BRs in the brain and their underlying mechanism in neuropathologic diseases, including epilepsy, pain regulation, depression, anxiety and drug addiction, revealed by recent studies. (E) It remains unclear whether GABA_BRs represent a major pharmacological target for treating BE‐like behaviors, food addiction, and imbalanced diet‐related overweight and obesity.

FIGURE 2

Chemical structures of representative full agonists, partial agonists, antagonists, and allosteric modulators of GABA_BRs. PAM is a positive allosteric modulator of GABA_BR. The structures of these GABA_BR‐targeting chemical compounds were verified by recent reports and study results.

FIGURE 3

Neuromodulatory effects of GABA_BRs on normal feeding behaviors and related neural circuits in the brain different regions of CNS. Evidence has shown that activation of GABA_BRs in different regions of the CNS significantly regulates feeding behaviors under normal conditions.

FIGURE 4

Effects of GABA_BRs on binge eating, food addiction, and obesity through central and peripheral regulation. On one hand, GABAergic neurons and GABA_BR may play a vital role in the regulation of energy homeostasis and feeding via the central hypothalamic (leptin, MCH, and CCK) and reward systems (NAc and VTA) and inhibition of food craving, reward abnormalities, and control‐decision imbalance in feeding behaviors (mPFC/OFC); on the other hand, regulation of GABA_BRs may be associated with peripheral vagal neuromodulation and regulation, which needs to further explore. These findings imply the potential of GABA_BR‐targeting strategies in the treatment of BE, food addiction, and obesity.

FIGURE 5

Regulated sites and signaling pathways and therapeutic prospects of strategies targeting GABA_BRs for the treatment of binge eating, food addiction and obesity. (A) The orthosteric ligand recognition site of GB1 binds to its ligands such as GABA and baclofen. (B) The allosteric ligand recognition site of GB2 binds to its allosteric modulators, such as GS39783. (C) Potential phosphorylation sites of the downstream GABA_BRs, including Ser867 of GB1, which is phosphorylated by CAMKII and Ser783 of GB2, which is phosphorylated by AMPK, and sites in other regulatory 14‐3‐3‐ζ proteins. (D) PP2A regulates downstream GABA_BRs via dephosphorylation. Small peptides and compounds exert marked regulatory effects.