User:Rana Saad/The human GABAb receptor

Introduction

γ-Aminobutyric acid (GABA) is the major inhibitory neurotransmitter in the central nervous system (CNS). It plays a key role in modulating neuronal activity since it binds to specific transmembrane receptors (GABA_A,GABA_B and GABA_C) in the plasma membrane of both pre- and postsynaptic neuronal level.

The mammalian GABA_B receptor is a class C G-protein coupled receptor^[1]. Its structure is similar to the metabotropic glutamate receptors (mGluR) ligand binding domain. The GABA_B receptor is central to inhibitory neurotransmission in the brain and so is considered a good candidate for treatments against alcoholism, stress and a number of brain diseases^[2].

The GABA_B receptor causes the opening of the K⁺ channels in the postsynaptic membrane, bringing the neuron closer to the equilibrium potential of K⁺, producing hyperpolarization. As a result, the Ca⁺² channels in the presynaptic terminal close, and neurotransmitter release stops. In addition GABA_B receptor function lead to reduce the activity of adenylyl cyclase and decrease the cell’s conductance to Ca⁺².[1].

Structure

GABA_B receptor functions as an obligatory heterodimer subunit of GABA_B1 (GBR1) and GABA_B2 (GBR2). GBR1 (blue) is responsible for ligand-binding (chain A). GBR2 (green), on the other hand, is responsible for the G protein coupling (chain B). The GABA_B receptor is one of only a few obligate receptor heterodimer currently known. There is no crystal or NMR structure of the complete receptor since it have extracellular and inter cellular regions.

The formation of a functional GABA_B receptor requires the heterodimeric assembly of GBR1 and GBR2 receptor subunits. Both consist of a seven-helix transmembrane domain composed of a large an N-terminal extracellular domain, venus flytrap (VFT), it is called like this because it is like the venus flytrap while binding agonist and antagonist, and a C-terminal intracellular domain which is responsible for GABA_B receptor heterodimerization.

The extracellular domain VFT

The VFT contains two lobe-shaped domains: LB1 and LB2, which are connected by three short loops. LB1 and LB2 are ^[3].

The agonist and antagonist binding

All of the agonists and antagonists bind the extracellular VFT module situated at the crevice between the LB1 and LB2 domains of the GBR1 subunit.

Both lobes LB1 and LB2 resdues of GBR1 interact with the GABA_B agonsits such as: GABA,baclofen. as a results of this interacting closed conformation will be stabilized when (PDB 4MS3) or (PDB 4MS4) and other agonists.

GABA_B antgonists such as: saclofen, CGP46381, phaclofen, CGP35348 and CGP54626, mostly intercat with LB1 resduses of GBR1. both ends of the antagonist bind the LB1, which produce open confirmation of GBR1. it is very easy to notice the open confirmation when : (PDB 4MQF). (PDB 4MS1). (PDB 4MRM). (PDB 4MR8). (PDB 4MR7).

The intercellular dimerization motif

When the GBR1 subunit is expressed alone, it is trapped in vesicles within the cell, whereas the GBR2 alone is expressed on the cell surface, but cannot bind GABA or activate G proteins. When both receptor subunits are expressed in the same cell, the receptor interact through ^[4][5] (PDB 4PAS) in their carboxyl tails. They are then expressed on the cell surface, bind GABA and activate G proteins. This domain is shaped by and is stabilized by ^[6].

Mutagenesis studies of GBR1 and GBR2 in the extracellular domain VFT

Mutagenesis studies in GBR1 subunit [2]

, , : Abolishes signaling via G-proteins and antagonist binding.

: Slightly decreases signaling via G-proteins.

: Decreases signaling via G-proteins.

: Strongly reduces signaling via G-proteins and abolishes antagonist binding.

: Strongly reduces signaling via G-proteins, no effect on antagonist binding.

Mutagenesis studies in GBR2 subunit [3]

: Decreases signaling via G-proteins.

References

1. ↑ Stevens RC, Cherezov V, Katritch V, Abagyan R, Kuhn P, Rosen H, Wuthrich K. The GPCR Network: a large-scale collaboration to determine human GPCR structure and function. Nat Rev Drug Discov. 2013 Jan;12(1):25-34. doi: 10.1038/nrd3859. Epub 2012 Dec, 14. PMID:23237917 doi:http://dx.doi.org/10.1038/nrd3859
2. ↑ Addolorato G, Leggio L, Cardone S, Ferrulli A, Gasbarrini G. Role of the GABA(B) receptor system in alcoholism and stress: focus on clinical studies and treatment perspectives. Alcohol. 2009 Nov;43(7):559-63. doi: 10.1016/j.alcohol.2009.09.031. PMID:19913201 doi:http://dx.doi.org/10.1016/j.alcohol.2009.09.031
3. ↑ Geng Y, Bush M, Mosyak L, Wang F, Fan QR. Structural mechanism of ligand activation in human GABA(B) receptor. Nature. 2013 Dec 12;504(7479):254-9. doi: 10.1038/nature12725. Epub 2013 Dec 4. PMID:24305054 doi:http://dx.doi.org/10.1038/nature12725
4. ↑ Burmakina S, Geng Y, Chen Y, Fan QR. Heterodimeric coiled-coil interactions of human GABAB receptor. Proc Natl Acad Sci U S A. 2014 Apr 28. PMID:24778228 doi:http://dx.doi.org/10.1073/pnas.1400081111
5. ↑ Pierce KL, Premont RT, Lefkowitz RJ. Seven-transmembrane receptors. Nat Rev Mol Cell Biol. 2002 Sep;3(9):639-50. PMID:12209124 doi:http://dx.doi.org/10.1038/nrm908
6. ↑ Burmakina S, Geng Y, Chen Y, Fan QR. Heterodimeric coiled-coil interactions of human GABAB receptor. Proc Natl Acad Sci U S A. 2014 Apr 28. PMID:24778228 doi:http://dx.doi.org/10.1073/pnas.1400081111