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).
View original pathway at Reactome.
Khan ZU, Fernando LP, Escribá P, Busquets X, Mallet J, Miralles CP, Filla M, De Blas AL.; ''Antibodies to the human gamma 2 subunit of the gamma-aminobutyric acidA/benzodiazepine receptor.''; PubMedEurope PMCScholia
Schofield PR, Pritchett DB, Sontheimer H, Kettenmann H, Seeburg PH.; ''Sequence and expression of human GABAA receptor alpha 1 and beta 1 subunits.''; PubMedEurope PMCScholia
Wingrove P, Hadingham K, Wafford K, Kemp JA, Ragan CI, Whiting P.; ''Cloning and expression of a cDNA encoding the human GABA-A receptor alpha 5 subunit.''; PubMedEurope PMCScholia
Jacob TC, Moss SJ, Jurd R.; ''GABA(A) receptor trafficking and its role in the dynamic modulation of neuronal inhibition.''; PubMedEurope PMCScholia
Bettler B, Kaupmann K, Mosbacher J, Gassmann M.; ''Molecular structure and physiological functions of GABA(B) receptors.''; PubMedEurope PMCScholia
Cutting GR, Curristin S, Zoghbi H, O'Hara B, Seldin MF, Uhl GR.; ''Identification of a putative gamma-aminobutyric acid (GABA) receptor subunit rho2 cDNA and colocalization of the genes encoding rho2 (GABRR2) and rho1 (GABRR1) to human chromosome 6q14-q21 and mouse chromosome 4.''; PubMedEurope PMCScholia
Garrett KM, Duman RS, Saito N, Blume AJ, Vitek MP, Tallman JF.; ''Isolation of a cDNA clone for the alpha subunit of the human GABA-A receptor.''; PubMedEurope PMCScholia
Taussig R, Iñiguez-Lluhi JA, Gilman AG.; ''Inhibition of adenylyl cyclase by Gi alpha.''; PubMedEurope PMCScholia
Hadingham KL, Wingrove P, Le Bourdelles B, Palmer KJ, Ragan CI, Whiting PJ.; ''Cloning of cDNA sequences encoding human alpha 2 and alpha 3 gamma-aminobutyric acidA receptor subunits and characterization of the benzodiazepine pharmacology of recombinant alpha 1-, alpha 2-, alpha 3-, and alpha 5-containing human gamma-aminobutyric acidA receptors.''; PubMedEurope PMCScholia
Bailey ME, Albrecht BE, Johnson KJ, Darlison MG.; ''Genetic linkage and radiation hybrid mapping of the three human GABA(C) receptor rho subunit genes: GABRR1, GABRR2 and GABRR3.''; PubMedEurope PMCScholia
Gerhardt MA, Neubig RR.; ''Multiple Gi protein subtypes regulate a single effector mechanism.''; PubMedEurope PMCScholia
Kleuss C, Raw AS, Lee E, Sprang SR, Gilman AG.; ''Mechanism of GTP hydrolysis by G-protein alpha subunits.''; PubMedEurope PMCScholia
Edenberg HJ, Dick DM, Xuei X, Tian H, Almasy L, Bauer LO, Crowe RR, Goate A, Hesselbrock V, Jones K, Kwon J, Li TK, Nurnberger JI, O'Connor SJ, Reich T, Rice J, Schuckit MA, Porjesz B, Foroud T, Begleiter H.; ''Variations in GABRA2, encoding the alpha 2 subunit of the GABA(A) receptor, are associated with alcohol dependence and with brain oscillations.''; PubMedEurope PMCScholia
Zhu Y, Ripps H, Qian H.; ''A single amino acid in the second transmembrane domain of GABA rho receptors regulates channel conductance.''; PubMedEurope PMCScholia
Clark MJ, Traynor JR.; ''Mediation of adenylyl cyclase sensitization by PTX-insensitive GalphaoA, Galphai1, Galphai2 or Galphai3.''; PubMedEurope PMCScholia
White JH, Wise A, Main MJ, Green A, Fraser NJ, Disney GH, Barnes AA, Emson P, Foord SM, Marshall FH.; ''Heterodimerization is required for the formation of a functional GABA(B) receptor.''; PubMedEurope PMCScholia
Yang W, Drewe JA, Lan NC.; ''Cloning and characterization of the human GABAA receptor alpha 4 subunit: identification of a unique diazepam-insensitive binding site.''; PubMedEurope PMCScholia
Cramer NP, Best TK, Stoffel M, Siarey RJ, Galdzicki Z.; ''GABAB-GIRK2-mediated signaling in Down syndrome.''; PubMedEurope PMCScholia
Hadingham KL, Garrett EM, Wafford KA, Bain C, Heavens RP, Sirinathsinghji DJ, Whiting PJ.; ''Cloning of cDNAs encoding the human gamma-aminobutyric acid type A receptor alpha 6 subunit and characterization of the pharmacology of alpha 6-containing receptors.''; PubMedEurope PMCScholia
Wagstaff J, Chaillet JR, Lalande M.; ''The GABAA receptor beta 3 subunit gene: characterization of a human cDNA from chromosome 15q11q13 and mapping to a region of conserved synteny on mouse chromosome 7.''; PubMedEurope PMCScholia
Hadingham KL, Wingrove PB, Wafford KA, Bain C, Kemp JA, Palmer KJ, Wilson AW, Wilcox AS, Sikela JM, Ragan CI.; ''Role of the beta subunit in determining the pharmacology of human gamma-aminobutyric acid type A receptors.''; PubMedEurope PMCScholia
Fowler CE, Aryal P, Suen KF, Slesinger PA.; ''Evidence for association of GABA(B) receptors with Kir3 channels and regulators of G protein signalling (RGS4) proteins.''; PubMedEurope PMCScholia
Dessauer CW, Chen-Goodspeed M, Chen J.; ''Mechanism of Galpha i-mediated inhibition of type V adenylyl cyclase.''; PubMedEurope PMCScholia
Hadingham KL, Wafford KA, Thompson SA, Palmer KJ, Whiting PJ.; ''Expression and pharmacology of human GABAA receptors containing gamma 3 subunits.''; PubMedEurope PMCScholia
Xie K, Allen KL, Kourrich S, Colón-Saez J, Thomas MJ, Wickman K, Martemyanov KA.; ''Gbeta5 recruits R7 RGS proteins to GIRK channels to regulate the timing of neuronal inhibitory signaling.''; PubMedEurope PMCScholia
Francken BJ, Jurzak M, Vanhauwe JF, Luyten WH, Leysen JE.; ''The human 5-ht5A receptor couples to Gi/Go proteins and inhibits adenylate cyclase in HEK 293 cells.''; PubMedEurope PMCScholia
Bonnert TP, McKernan RM, Farrar S, le Bourdellès B, Heavens RP, Smith DW, Hewson L, Rigby MR, Sirinathsinghji DJ, Brown N, Wafford KA, Whiting PJ.; ''theta, a novel gamma-aminobutyric acid type A receptor subunit.''; PubMedEurope PMCScholia
Cutting GR, Lu L, O'Hara BF, Kasch LM, Montrose-Rafizadeh C, Donovan DM, Shimada S, Antonarakis SE, Guggino WB, Uhl GR.; ''Cloning of the gamma-aminobutyric acid (GABA) rho 1 cDNA: a GABA receptor subunit highly expressed in the retina.''; PubMedEurope PMCScholia
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.
GABA A (rho) receptors are highly expressed in the retina and are functional homopentamers of rho subunits. These receptors were formerly called GABA C receptors.
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).
Try the New WikiPathways
View approved pathways at the new wikipathways.org.Quality Tags
Ontology Terms
Bibliography
History
External references
DataNodes
(i):GTP:Adenylate
cyclaseG-protein beta-gamma and Kir3
channel complexG-protein
beta-gamma complexAnnotated Interactions
(i):GTP:Adenylate
cyclase(i):GTP:Adenylate
cyclaseG-protein beta-gamma and Kir3
channel complexG-protein beta-gamma and Kir3
channel complexG-protein
beta-gamma complexG-protein
beta-gamma 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).
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).