The neurotransmitter in the synaptic cleft released by the pre-synaptic neuron binds specific receptors located on the post-synaptic terminal. These receptors are either ion channels or G protein coupled receptors that function to transmit the signals from the post-synaptic membrane to the cell body.
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CaMKII is composed of a homo or hetero dodecamer of four subunits apha, beta, delta and gamma. In a heteromultimer the ratio of alpha to beta may vary from 6;1, 3:1 or 1:1.
CaMKII is composed of a homo or hetero dodecamer of four subunits apha, beta, delta and gamma. In a heteromultimer the ratio of alpha to beta may vary from 6;1, 3:1 or 1:1.
GRIK2 is edited at the Q/R site at 621 where the glutamine is edited to arginine. GRIK2 is also edited at 571 (Y/C) where a tyrosine residue is changed to cysteine and 567 (I/V) where an isoleucine is changed to valine. All three sites are edited postranscriptionally. A fully edited GRIK2 at all three sites is totally impermeable to calcium ions.
Kainate receptors are formed by the assembly of four subunits. GluR5-7 (GRIK, glutamate receptor, ionotropic Kainate 1-3) form functional homomers whereas, KA1 and KA2 or GRIK4,5 form functional heteromers with GRIK1/2/3.
Kainate receptor subunits bind Cl- ion in the anion binding site in the ligand binding domain. The dimer is stabilized by the presence of one Cl- ion which binds within the dimer interface.
NMDAR complex consists of two NR1 subunits and two NR2 subunits. Each subunit has extensive C terminal tail that is modified by series of protein kinases and protein phosphatases. The NR1 subunits binds co-agonist glycine while the NR2 subunit binds glutamate. Hence the activation of NR1/NR2 containing NMDA receptor complexes are activated upon depolarization of the membrane and binding of both glycine and glutamate. The dual requirement of membrane depolarization and agonist binding facilitate coincidence detection by NMDA receptors that ensures activation of both pre-synaptic and post-synaptic cell. NR1/NR2 containing NMDA receptors are highly Ca2+ permeable and subjected to a voltage dependent Mg2+ block.
Kainate receptors are formed by the assembly of four subunits. GluR5-7 (GRIK, glutamate receptor, ionotropic Kainate 1-3) form functional homomers whereas, KA1 and KA2 or GRIK4,5 form functional heteromers with GRIK1/2/3.
Kainate receptor subunits bind Cl- ion in the anion binding site in the ligand binding domain. The dimer is stabilized by the presence of one Cl- ion which binds within the dimer interface.
Autophosphorylation of the N-terminus Ser12-Ser13 is required for full activation after Ca2+/calmodulin binding and phosphorylation of the Ca2+/calmodulin-bound enzyme on Thr200 by a Ca2+/calmodulin-dependent protein kinase kinase.
CaMKIV becomes fully activated after a three-step mechanism: Upon a transient increase in intracellular calcium, calcium-bound calmodulin (Ca2+/CaM) binds to its autoregulatory domain, which relieves intersteric inhibition. An activating protein kinase, calcium/calmodulin-dependent protein kinase kinase (CaMKK), binds to the Ca2+/CaM:CaMKIV complex and phosphorylates CaMKIV on a threonine residue in the activation loop. After full activation by the three-step mechanism mentioned above, the activity of CaMKIV becomes autonomous and no longer requires bound Ca2+/CaM. This activity is required for CaMKIV-mediated transcriptional regulation. The CaMKIV-associated PP2A then dephosphorylates CaMKIV, thereby terminating autonomous activity and CaMKIV-mediated gene transcription.
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.
Each AMPA receptor subunit binds one glutamate molecule in the ligand binding site in the N terminus. Each receptor is capable of binding four glutamate molecule, however, channel opens when two sites are occupied by the ligand and the current increases with increased ligand binding. Ca permeable AMPA receptors containing homomers of GluR1 or heteromers containing GluR1, GluR3 and GluR4 conduct Ca upon glutamate or agonist namely AMPA (alpha-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid) binding. Calcium permeable AMPA receptors conduct Ca and other cations such as Na. The inonic flux leads to Ca or Na currents that leads to either increase in the intracellular Ca concentration leading to further Ca-dependent signaling or increase in depolarization that opens voltage gated channels such as NMDA receptors that require both membrane depolarization and glutamate binding for activation.
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.
GluR2 containing AMPA receptors are constitutively recycled between the endosome membrane and the plasma membrane. GRIP and PICK compete for the binding to the C tail of GluR2. Once the GluR2 containing AMPA receptors are in the plasmamembrane, phosphorylation of GluR2 at S880 by PKC causes disruption of GRIP interaction, but not PICK interaction which facilitates internalization of GluR2 containing AMPA receptors into endosomes.
Constitutively recycling GluR2 containing AMPA receptors in the plasmamembrane are stabilized by the action of NSF ATPase activity which disassociates PICK from GluR2 thereby retaining AMPA receptors in the plasmamembrane.
GluR2 containing AMPA receptors are trafficked to the plasmamembrane by the activation of Ca activated PKC that binds PICK.The PICK interaction delivers GluR2 containing AMPA receptors to the Plasmamembrane. This reaction is a part of constitutive recycling of AMPA receptor that delivers the AMPA receptors from the endosome to the plasmamembrane and back to endosome from the plasmamembrane.
Each AMPA receptor subunit binds one glutamate molecule in the ligand binding site in the N terminus. Each receptor is capable of binding four glutamate molecule, however, channel opens when two sites are occupied by the ligand and the current increases with increased ligand binding. Ca permeable AMPA receptors containing homomers of GluR1 or heteromers containing GluR1, GluR3 and GluR4 conduct Ca upon glutamate or agonist namely AMPA (alpha-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid) binding. Calcium permeable AMPA receptors conduct Ca and other cations such as Na. The inonic flux leads to Ca or Na currents that leads to either increase in the intracellular Ca concentration leading to further Ca-dependent signaling or increase in depolarization that opens voltage gated channels such as NMDA receptors that require both membrane depolarization and glutamate binding for activation.
GluR1-containing AMPA receptors are delivered to the synapses in an activity dependent manner. GluR1 trafficking is controlled by protein- protein interactions with 4.1N/G protein, SAP97 and by intricate regulation of phosphorylation of GluR1 at several phosphorylation sites in the C tail. GluR1 has four phosphorylation sites; serine 818 (S818) is phosphorylated by PKC, necessary for LTP, serine 831 (S831) is phosphorylated by CaMKII and increases the delivery of receptors to the synapse and also increases their single channel conductance, Threonine (T840) is implicated in LTP and serine 845 (S845) phosphorylated by PKA regulates open channel probability and also by cGKII, a cyclic GMP activated kinase, that increases the surface expression of GluR1. GluR1 insertion into synapse by CaMKII may induce LTP. CaMKII is a Ca/calmodulin dependent kinase that is activated upon increases in the Ca ion concentration during postsynaptic activity through NMDA receptors. The increase in GluR1-containing AMPA receptor population at the synapse results in enhancement of excitatory post synaptic potential (EPSC) which forms the basis of Long term potentiation (LTP). LTP is one form of synaptic plasticity that is involved in memory and learning. The increase in the GluR1 containing AMPA receptors and their activity leads to rise in intracellular Ca which induces signaling pathways that in turn promote switch in the type of AMPA receptors (Ca impermeable) thereby limiting the Ca increase and preventing cell death.
Each AMPA receptor subunit binds one glutamate molecule in the ligand binding site in the N terminus. Each receptor is capable of binding four glutamate molecules however, channel opens when two sites are occupied by the ligand and the current increases with increased ligand binding. Ca impermeable AMPA receptors containing GluR2 subunit conduct Na currents upon activation by either glutamate binding or agonist, AMPA (alpha-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid) binding. The Na currents mainly lead to depolarization of the membrane leading to activation of voltage gated channels such as NMDA receptors that require both agonist binding and depolarization for their activation.
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.
NMDA receptors are activated upon binding of two ligands, glutamate and glycine. The activation leads to Ca2+ influx into the post-synaptic cell. The local rise in the Ca2+ ion concentration further leads to activation of several Ca2+ dependent pathways leading to long term changes in the synapse.
NMDA receptors are activated in a two step mechanism; first by the removal of the voltage dependent Mg2+ block and then by the ligand dependent activation of the unblocked NMDA receptor. At resting membrane potential NMDA receptors can not be activated by ligand alone due to the presence of Mg2+ ion in the pore of the channel. Due to the activation of other membrane resident channels that allow the influx of Na+ the membrane is depolarized which triggers the removal of Mg2+ form the NMDA receptor pore. Once the Mg2+ is expelled NMDA receptors are ready to be activated by the agonist (glutamate) and the co-agonist (glycine).
Ca2+ fluxes through NMDA receptors in the post-synaptic neuron facilitate binding of Ca2+/Calmodulin to adenylate cyclase type 1, 3 or 8, resulting in its activation. Once activated, cAMP is produced which further activates PKA.
CaMKII gets activated upon Ca2+ influx through the NMDA receptor and moves from plasma membrane to cytoplasm and then nucleus where it phosphorylates CREB at serine 133.
Membrane depolarization occurs due to glutamate dependent activation of Ca-impermeable AMPA receptors, which permit the influx of Na+ ions. The depolarization triggers the removal of Mg2+ from the NMDA receptor pore to facilitate its activation. Therefore activation of AMPA receptors by glutamate precedes activation of NMDA receptors.
CaMKII is an important regulator of neuronal plasticity. CaMKII shows distinct subcellular localization and acts quickly in a spatio-temporal manner. CaMKII shows fast synaptic localization upon synaptic activity and also nuclear localization, where it phosphorylates CREB at serine 133 to activate transcription of set of genes that results in long lasting structural changes at the synapse.
Raf is a downstream effector of ras. Raf is activated upon phosphorylation at S338, oligomerization and membrane localization. Membrane localization is facilitated by ras. Interaction of ras with raf is a necessary step but not sufficient for raf activation. Other unknown protein partner interactions are required for raf activation. Raf further activates MAP kinase.
Nuclear targeting of CaMKII depends on several factors including the phosphorylation in the regulatory domain of CaMKII and induction of other signal transduction pathways.
Protein kinase A has two regulatory subunits and two catalytic subunits which are held together to form the holoenzyme and is activated upon binding of cAMP within the regulatory subunits. Once cAMP binds the regulatory subunits, the catalytic subunits are released to carry out phosphorylation of CREB at serine133.
NMDA receptors require binding of two ligands; the agonist, glutamate and co-agonist, glycine. The N terminal extracellular ligand binding domain in NR1 subunits binds co-agonist glycine and the N terminal extracellular ligand binding domain in NR2 binds glutamate.
Binding of RasGRF to Ca2+/Calmodulin in the presence of high Ca2+ leads to the activation of Ras. Activation of Ras involves the exchange of GDP for GTP.
MAPK/ERK is phosphorylated at threonine 185 and tyrosine 187 by membrane associated activated raf kianse leading to the activation of MAPK/ERK kinase.
The activated MAPK/ERK in turn activates ribosomal S6 kinase.
CaMKII is fully activated upon Ca2+/Calmodulin binding. In addition to Ca2+/Calmodulin activation, CaMKII undergoes multiple autophosphorylation events leading Ca2+/Calmodulin independent activity of the enzyme.
CaMKK is fully activated upon binding Ca2+/Calmodulin after intracellular Ca2+ levels increase. Once CaMKK binds Ca2+/Calmodulin it autophosphorylates, resulting in activation. CaMKK is negatively regulated by phosphorylation of S74 and T108 by PKA. Once activated CaMKK phosphorylates CaMKIV in a Ca2+/Calmodulin dependent manner.
PDK1 activates ribosomal S6 kinase (RSK) by phosphorylating S221. The binding site for PDK1 on RSK is available after RSK phosphorylation by MAPK/ERK. PDK1 is present in the activated form at the plasma membrane where the phosphorylation occurs. The activation of RSK occurs in the cytoplasm, plasma membrane and in the nucleus where it finally activates CREB by phosphorylation.
Activated CaMKIV phosphorylates CREB at S133 thereby initiating the transcription of CREB regulated set of genes leading to protein synthesis and long lasting changes that underlie synaptic plasticity.
The activation of Kainate receptors by glutamate in the postsynaptic neuron leads to influx of Na+ ions resulting in depolarization of the postsynaptic membrane.
Kainate receptor activation activates G protein coupled receptors involving the release of Ca2+ from the intracellular stores. This activity of Kainate receptors is independent of ionic influx and regulates both glutamate release by the pyramidal neurons and gama-aminobutyric acid release by the internuerons.
Kainate receptors that are assembled with subunits GRIK1-5, are Ca2+ permeable if GRIK1 and GRIK2 are not edited at the Q/R or other sites. These channels permit Ca2+ upon activation by glutamate or other agonists.
Nicotinic acetylcholine receptors bind two molecules of ligand, acetylcholine, in the alpha beta interface in receptors containing heteromeric subunits or in the interface of 2 aplha subunits in receptors containing homomeric subunits.
Acetylcholine binding activates postsynaptic acetylchloine receptors that show Ca2+ currents which facilitate the process of long term potentiation (LTP).
Nicotinic acetylcholine receptors are activated upon ligand binding which opens the acetylcholine channels and permits Ca2+ and Na+ ion influx depending on the subunit composition and stoichiometry of the subunits. The ratio of Ca2+ to Na+ ion influx varies making the receptors either highly Na+ permeable or Ca2+ permeable.
Nicotinic acetylcholine receptors containing aplha4(2) beta2 (3) and alpha3(2) beta4(3) are selectively highly Na+ permeable upon activation of these receptors by acetylcholine.
Nicotinic acetylcholine receptors bind two molecules of ligand, acetylcholine, in the alpha beta interface in receptors containing heteromeric subunits or in the interface of 2 aplha subunits in receptors containing homomeric subunits.
Nicotinic acetylcholine receptors bind two molecules of ligand, acetylcholine, in the alpha beta interface in receptors containing heteromeric subunits or in the interface of 2 aplha subunits in receptors containing homomeric subunits.
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.
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) and 2 gamma subunits (GABRG) (Khan et al. 1993, Hadingham et al. 1995) characterized. GABA(A) functions as a heteropentamer, the most common structure being 2 alpha subunits, 2 beta subunits and a gamma subunit (2GABRA:2GABRB:GABRG). Upon binding of GABA, this complex conducts chloride ions through its pore, resulting in hyperpolarization 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).
Original Pathway at Reactome: http://www.reactome.org/PathwayBrowser/#DB=gk_current&FOCUS_SPECIES_ID=48887&FOCUS_PATHWAY_ID=112314
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2GABRB GABRG
GABAAnnotated Interactions
2GABRB GABRG
GABAThe activation leads to Ca2+ influx into the post-synaptic cell. The local rise in the Ca2+ ion concentration further leads to activation of several Ca2+ dependent pathways leading to long term changes in the synapse.
These channels permit Ca2+ upon activation by glutamate or other agonists.