Molecular mechanisms of metabotropic GABA _B receptor function

Abstract

Metabotropic γ-aminobutyric acid G protein–coupled receptors (GABAB) represent one of the two main types of inhibitory neurotransmitter receptors in the brain. These receptors act both pre- and postsynaptically by modulating the transmission of neuronal signals and are involved in a range of neurological diseases, from alcohol addiction to epilepsy. A series of recent cryo-EM studies revealed critical details of the activation mechanism of GABAB. Structures are now available for the receptor bound to ligands with different modes of action, including antagonists, agonists, and positive allosteric modulators, and captured in different conformational states from the inactive apo to the fully active state bound to a G protein. These discoveries provide comprehensive insights into the activation of the GABAB receptor, which not only broaden our understanding of its structure, pharmacology, and physiological effects but also will ultimately facilitate the discovery of new therapeutic drugs and neuromodulators.

GABAB‐ and GABAA‐receptor‐mediated regulation of Up and Down states across development

“…Possible explanations for this bimodal effect can be inferred from previous studies. GABA B receptors can act either postsynaptically, by inducing neuron hyperpolarization through inwardly rectifying K + channels (GIRK), or presynaptically, by blocking neurotransmitter release through inhibiting voltage‐gated Ca 2+ channels (Shaye et al., 2021). Our results show that the participation of GABA B receptors in modulating the termination of Up states is a robust, developmentally conserved mechanism.…”

Innovative treatments for epilepsy: Venom peptides, cannabinoids, and neurostimulation

“…GABA is a neurotransmitter which is majorly involved with inhibitory receptors, and it plays a key role on CNS synapses. GABA receptors can be classified as metabotropic receptors, such as GABA‐B, or ionotropic, represented by GABA‐A and GABA‐C, being that the latter is now categorized as GABA‐Aρ, a subtype of GABA‐A receptors (Sallard et al, 2021; Shaye et al, 2021; Wu & Sun, 2015).…”

“…GABA‐B, on the other hand, is a heterodimer, divided in two subunits, GABA‐B1 and GABA‐B2. Each subunit has an extracellular Venus flytrap domain, associated with a seven transmembrane segment domain via a short linker—besides that, there is also an intracellular coiled‐coil domain that stabilizes heterodimerization (Evenseth et al, 2020; Shaye et al, 2021).…”

Analgesic α-Conotoxin Binding Site on the Human GABAB Receptor

“…Recent cryo-EM studies of the GABA B R have been elucidated for the receptor bound to a variety of different ligands. The observed structures capture alternate conformations from the inactive apo state to the fully active G protein-bound state (see Shaye et al, 2021). The N-terminal extracellular domains of B1 and B2, each consist of two lobes, LB1 and LB2, of the "Venus Flytrap domains" (VFTs), which trap the ligand in its orthosteric binding site situated on B1 at the B1/B2 interface.…”