6wiv
From Proteopedia
Structure of human GABA(B) receptor in an inactive state
Structural highlights
Function[GABR1_HUMAN] Component of a heterodimeric G-protein coupled receptor for GABA, formed by GABBR1 and GABBR2. Within the heterodimeric GABA receptor, only GABBR1 seems to bind agonists, while GABBR2 mediates coupling to G proteins. Ligand binding causes a conformation change that triggers signaling via guanine nucleotide-binding proteins (G proteins) and modulates the activity of down-stream effectors, such as adenylate cyclase. Signaling inhibits adenylate cyclase, stimulates phospholipase A2, activates potassium channels, inactivates voltage-dependent calcium-channels and modulates inositol phospholipid hydrolysis. Calcium is required for high affinity binding to GABA. Plays a critical role in the fine-tuning of inhibitory synaptic transmission. Pre-synaptic GABA receptor inhibits neurotransmitter release by down-regulating high-voltage activated calcium channels, whereas postsynaptic GABA receptor decreases neuronal excitability by activating a prominent inwardly rectifying potassium (Kir) conductance that underlies the late inhibitory postsynaptic potentials. Not only implicated in synaptic inhibition but also in hippocampal long-term potentiation, slow wave sleep, muscle relaxation and antinociception. Activated by (-)-baclofen, cgp27492 and blocked by phaclofen.[1] [2] [3] [4] Isoform 1E may regulate the formation of functional GABBR1/GABBR2 heterodimers by competing for GABBR2 binding. This could explain the observation that certain small molecule ligands exhibit differential affinity for central versus peripheral sites.[5] [6] [7] [8] [GABR2_HUMAN] Component of a heterodimeric G-protein coupled receptor for GABA, formed by GABBR1 and GABBR2. Within the heterodimeric GABA receptor, only GABBR1 seems to bind agonists, while GABBR2 mediates coupling to G proteins. Ligand binding causes a conformation change that triggers signaling via guanine nucleotide-binding proteins (G proteins) and modulates the activity of down-stream effectors, such as adenylate cyclase. Signaling inhibits adenylate cyclase, stimulates phospholipase A2, activates potassium channels, inactivates voltage-dependent calcium-channels and modulates inositol phospholipid hydrolysis. Plays a critical role in the fine-tuning of inhibitory synaptic transmission. Pre-synaptic GABA receptor inhibits neurotransmitter release by down-regulating high-voltage activated calcium channels, whereas postsynaptic GABA receptor decreases neuronal excitability by activating a prominent inwardly rectifying potassium (Kir) conductance that underlies the late inhibitory postsynaptic potentials. Not only implicated in synaptic inhibition but also in hippocampal long-term potentiation, slow wave sleep, muscle relaxation and antinociception.[9] [10] [11] [12] Publication Abstract from PubMedThe human GABAB receptor-a member of the class C family of G-protein-coupled receptors (GPCRs)-mediates inhibitory neurotransmission and has been implicated in epilepsy, pain and addiction(1). A unique GPCR that is known to require heterodimerization for function(2-6), the GABAB receptor has two subunits, GABAB1 and GABAB2, that are structurally homologous but perform distinct and complementary functions. GABAB1 recognizes orthosteric ligands(7,8), while GABAB2 couples with G proteins(9-14). Each subunit is characterized by an extracellular Venus flytrap (VFT) module, a descending peptide linker, a seven-helix transmembrane domain and a cytoplasmic tail(15). Although the VFT heterodimer structure has been resolved(16), the structure of the full-length receptor and its transmembrane signalling mechanism remain unknown. Here we present a near full-length structure of the GABAB receptor at atomic resolution, captured in an inactive state by cryo-electron microscopy. Our structure reveals several ligands that preassociate with the receptor, including two large endogenous phospholipids that are embedded within the transmembrane domains to maintain receptor integrity and modulate receptor function. We also identify a previously unknown heterodimer interface between transmembrane helices 3 and 5 of both subunits, which serves as a signature of the inactive conformation. A unique 'intersubunit latch' within this transmembrane interface maintains the inactive state, and its disruption leads to constitutive receptor activity. Structure of human GABAB receptor in an inactive state.,Park J, Fu Z, Frangaj A, Liu J, Mosyak L, Shen T, Slavkovich VN, Ray KM, Taura J, Cao B, Geng Y, Zuo H, Kou Y, Grassucci R, Chen S, Liu Z, Lin X, Williams JP, Rice WJ, Eng ET, Huang RK, Soni RK, Kloss B, Yu Z, Javitch JA, Hendrickson WA, Slesinger PA, Quick M, Graziano J, Yu H, Fiehn O, Clarke OB, Frank J, Fan QR Nature. 2020 Jun 24. pii: 10.1038/s41586-020-2452-0. doi:, 10.1038/s41586-020-2452-0. PMID:32581365[13] From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine. See AlsoReferences
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Categories: Human | Large Structures | Cao, B | Chen, S | Clarke, O B | Eng, E T | Fan, Q R | Fiehn, O | Frangaj, A | Frank, J | Fu, Z | Geng, Y | Grassucci, R | Graziano, J | Hendrickson, W A | Huang, R K | Javitch, J A | Kloss, B | Kou, Y | Lin, X | Liu, J | Liu, Z | Mosyak, L | Park, J | Quick, M | Ray, K M | Rice, W J | Shen, T | Slavkovich, V N | Slesinger, P A | Soni, R K | Taura, J | Williams, J P | Yu, H | Yu, Z | Zuo, H | Class c gpcr | Gaba | Inhibitory neurotransmission | Membrane protein | Phospholipid
