Gamma aminobutyric acid (GABA) receptors are the major inhibitory receptors in human synapses. They are of two types. GABA A receptors are fast-acting ligand gated chloride ion channels that mediate membrane depolarization and thus inhibit neurotransmitter release (G Michels et al Crit Rev Biochem Mol Biol 42, 2007, 3-14). GABA B receptors are slow acting metabotropic Gprotein coupled receptors that act via the inhibitory action of their Galpha/Go subunits on adenylate cyclase to attenuate the actions of PKA. In addition, their Gbeta/gamma subunits interact directly with N and P/Q Ca2+ channels to decrease the release of Ca2+. GABA B receptors also interact with Kir3 K+ channels and increase the influx of K+, leading to cell membrane hyperpolarization and inhibition of channels such as NMDA receptors (A Pinard et al Adv Pharmacol, 58, 2010, 231-55).
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Binding of G beta gamma activates the GIRK/Kir3 channels that allow the efflux of K+ out of the cell resulting in a hyperpolarized membrane potential. This negative membrane potential prevents the activation of voltage dependent Ca2+ channels.
G proteins can deactivate themselves via their intrinsic GTPase activity, which hydrolyzes GTP to GDP. Effectors such as adenylate cyclase can increase the G protein GTPase rate, acting like GTPase-activating proteins (GAPs).
Once the intrinsic GTPase hydrolyzes GTP to GDP, Galpha-i dissociates from adenylate cyclase, allowing it to re-associate with G-beta-gamma and starting a new cycle.
G proteins can deactivate themselves via their intrinsic GTPase activity, which hydrolyzes GTP to GDP. Effectors such as adenylate cyclase can increase the G protein GTPase rate, acting like GTPase-activating proteins (GAPs).
G-proteins in the Gi class inhibit adenylate cyclase activity, decreasing the production of cAMP from ATP, which has many consequences but classically results in decreased activity of Protein Kinase A (PKA). cAMP also activates the cyclic nucleotide-gated ion channels, a process that is particularly important in olfactory cells.
Gamma-aminobutyric acid (GABA) is the chief inhibitory neurotransmitter in the mammalian central nervous system. GABA exerts its effects through two ligand-gated channels and a the GPCR GABAB (Kaupmann K et al, 1998), which acts through G proteins to regulate potassium and calcium channels. GABAB can only bind GABA once it forms a heterodimer composed of the GABABR1 and GABABR2 receptors (White JH et al, 1998). The effects of this dimer are mediated by coupling to the G protein alpha i subunit, which inhibits adenylyl cyclase (Odagaki & Koyama 2001).
Neuroplastin (NPTN) is a glycoprotein that belongs to the immunoglobulin (Ig) superfamily of cell adhesion molecules (CAMs). Together with basigin/CD147 and embigin, NPTN comprises the CD147 family (Iacono et al. 2007).
NPTN isoform p65 binds GABAA receptor subunits, co-localizing with alpha1 and alpha2, but not alpha3 subunits at GABAergic synapses and alpha5 subunits at extrasynaptic sites in cultures (Sarto-Jackson et al. 2012). GABAA receptors containing alpha1, 2 or 3 subunits are localized mainly at synaptic sites and interact with the scaffolding protein Gephyrin (GPHN), which anchors the receptor to the underlying postsynaptic complex and prevents their lateral diffusion (Kneussel & Loebrich 2007, Tretter et al. 2012). Receptors containing the alpha5 subunit are mainly extrasynaptic and link to the actin cytoskeleton via Radixin (Loebrich et al. 2006). NPTN p65 co-localization can be at several synaptic sites along the same dendrite, while absent from others. NPTN p65 shRNA caused diffuse alpha2 subunit staining which did not co-localize with vesicular inhibitory aa transporter, a presynaptic marker of GABAergic synapses (Sarto-Jackson et al. 2012). This suggests a functional role for NPTN p65 in regulating the composition and localization of GABAA receptors (Beesley et al. 2014). The absence of NPTN p65 causes early-onset sensorineural hearing loss and prevents normal synaptogenesis in cochleal inner hair cells (IHCs) (Carrott et al. 2016).
The GABA(A) receptor (GABR) family belongs to the ligand-gated ion channel superfamily (LGIC). Its endogenous ligand is gamma-aminobutyric acid (GABA), the major inhibitory neurotransmitter in the central nervous system. There are six alpha subunits (GABRA) (Garrett et al. 1988, Schofield et al. 1989, Hadingham et al. 1993, Edenberg et al. 2004, Hadingham et al. 1993, Yang et al. 1995, Wingrove et al. 1992, Hadingham et al. 1996), three beta subunits (GABRB) (Schofield et al. 1989, Hadingham et al. 1993, Wagstaff et al. 1991), 2 gamma subunits (GABRG) (Khan et al. 1993, Hadingham et al. 1995) and a theta subunit (Bonnert et al. 1999) characterised to date. GABA(A) functions as a heteropentamer, the most common structure being 2 alpha subunits, 2 beta subunits and a gamma subunit (2GABRA:2GABRB:GABRG). An alternative heteropentamer with much less affinity for GABA is 2GABRA:GABRB:GABRG:GABRQ (Bonnert et al. 1999). Upon binding of GABA, both GABR complexes conduct chloride ions through their pore, resulting in hyperpolarisation of the neuron. This causes an inhibitory effect on neurotransmission by reducing the chances of a successful action potential occurring.
The GABA(A)-rho receptor (GABRR) is expressed in many areas of the brain, but in contrast to other GABA(A) receptors, has especially high expression in the retina. It is functional as a homopentamer and is permeable to chloride ions when GABA binds to it (Cutting et al. 1991, Cutting et al. 1992, Bailey et al. 1990).
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DataNodes
(i):GTP:Adenylate
cyclaseG-protein beta-gamma and Kir3
channel complexAnnotated Interactions
(i):GTP:Adenylate
cyclase(i):GTP:Adenylate
cyclaseG-protein beta-gamma and Kir3
channel complexNPTN isoform p65 binds GABAA receptor subunits, co-localizing with alpha1 and alpha2, but not alpha3 subunits at GABAergic synapses and alpha5 subunits at extrasynaptic sites in cultures (Sarto-Jackson et al. 2012). GABAA receptors containing alpha1, 2 or 3 subunits are localized mainly at synaptic sites and interact with the scaffolding protein Gephyrin (GPHN), which anchors the receptor to the underlying postsynaptic complex and prevents their lateral diffusion (Kneussel & Loebrich 2007, Tretter et al. 2012). Receptors containing the alpha5 subunit are mainly extrasynaptic and link to the actin cytoskeleton via Radixin (Loebrich et al. 2006). NPTN p65 co-localization can be at several synaptic sites along the same dendrite, while absent from others. NPTN p65 shRNA caused diffuse alpha2 subunit staining which did not co-localize with vesicular inhibitory aa transporter, a presynaptic marker of GABAergic synapses (Sarto-Jackson et al. 2012). This suggests a functional role for NPTN p65 in regulating the composition and localization of GABAA receptors (Beesley et al. 2014). The absence of NPTN p65 causes early-onset sensorineural hearing loss and prevents normal synaptogenesis in cochleal inner hair cells (IHCs) (Carrott et al. 2016).