Neurotransmitter receptors and postsynaptic signal transmission (Homo sapiens)

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3, 4, 6, 9, 12...13, 17, 19cytosolGlutamate binding,activation of AMPAreceptors andsynaptic plasticityGLRA4 K+Ca2+Activation ofkainate receptorsupon glutamatebindingHTR3D Activation of NMDAreceptors andpostsynaptic eventsNa+GLRB GLRA3 Cl-GABA receptoractivationHTR3E HTR3B HTR3A GLRA1 HTR3 pentamer:5HTCl-Gly HTR3C Na+K+GLRA2 GLRA:GLRB:Gly5HT Acetylcholinebinding anddownstream eventsCa2+10, 14, 161, 2, 8, 11, 215, 7, 1518


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. View original pathway at:Reactome.


Pathway is converted from Reactome ID: 112314
Reactome version: 66
Reactome Author 
Reactome Author: Mahajan, SS

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  1. Bettler B, Kaupmann K, Mosbacher J, Gassmann M.; ''Molecular structure and physiological functions of GABA(B) receptors.''; PubMed Europe PMC
  2. Moss SJ, Smart TG.; ''Constructing inhibitory synapses.''; PubMed Europe PMC
  3. Miyake A, Mochizuki S, Takemoto Y, Akuzawa S.; ''Molecular cloning of human 5-hydroxytryptamine3 receptor: heterogeneity in distribution and function among species.''; PubMed Europe PMC
  4. Niesler B, Walstab J, Combrink S, Möller D, Kapeller J, Rietdorf J, Bönisch H, Göthert M, Rappold G, Brüss M.; ''Characterization of the novel human serotonin receptor subunits 5-HT3C,5-HT3D, and 5-HT3E.''; PubMed Europe PMC
  5. Lee HK.; ''Synaptic plasticity and phosphorylation.''; PubMed Europe PMC
  6. Wu ZS, Cheng H, Jiang Y, Melcher K, Xu HE.; ''Ion channels gated by acetylcholine and serotonin: structures, biology, and drug discovery.''; PubMed Europe PMC
  7. Cull-Candy S, Kelly L, Farrant M.; ''Regulation of Ca2+-permeable AMPA receptors: synaptic plasticity and beyond.''; PubMed Europe PMC
  8. Pinard A, Seddik R, Bettler B.; ''GABAB receptors: physiological functions and mechanisms of diversity.''; PubMed Europe PMC
  9. Barnes NM, Hales TG, Lummis SC, Peters JA.; ''The 5-HT3 receptor--the relationship between structure and function.''; PubMed Europe PMC
  10. Cohen S, Greenberg ME.; ''Communication between the synapse and the nucleus in neuronal development, plasticity, and disease.''; PubMed Europe PMC
  11. Padgett CL, Slesinger PA.; ''GABAB receptor coupling to G-proteins and ion channels.''; PubMed Europe PMC
  12. Barrera NP, Herbert P, Henderson RM, Martin IL, Edwardson JM.; ''Atomic force microscopy reveals the stoichiometry and subunit arrangement of 5-HT3 receptors.''; PubMed Europe PMC
  13. Grenningloh G, Schmieden V, Schofield PR, Seeburg PH, Siddique T, Mohandas TK, Becker CM, Betz H.; ''Alpha subunit variants of the human glycine receptor: primary structures, functional expression and chromosomal localization of the corresponding genes.''; PubMed Europe PMC
  14. Hardingham GE, Bading H.; ''Synaptic versus extrasynaptic NMDA receptor signalling: implications for neurodegenerative disorders.''; PubMed Europe PMC
  15. Kessels HW, Malinow R.; ''Synaptic AMPA receptor plasticity and behavior.''; PubMed Europe PMC
  16. Paoletti P, Bellone C, Zhou Q.; ''NMDA receptor subunit diversity: impact on receptor properties, synaptic plasticity and disease.''; PubMed Europe PMC
  17. Handford CA, Lynch JW, Baker E, Webb GC, Ford JH, Sutherland GR, Schofield PR.; ''The human glycine receptor beta subunit: primary structure, functional characterisation and chromosomal localisation of the human and murine genes.''; PubMed Europe PMC
  18. Jane DE, Lodge D, Collingridge GL.; ''Kainate receptors: pharmacology, function and therapeutic potential.''; PubMed Europe PMC
  19. Nikolic Z, Laube B, Weber RG, Lichter P, Kioschis P, Poustka A, Mülhardt C, Becker CM.; ''The human glycine receptor subunit alpha3. Glra3 gene structure, chromosomal localization, and functional characterization of alternative transcripts.''; PubMed Europe PMC
  20. Davies PA, Pistis M, Hanna MC, Peters JA, Lambert JJ, Hales TG, Kirkness EF.; ''The 5-HT3B subunit is a major determinant of serotonin-receptor function.''; PubMed Europe PMC
  21. Michels G, Moss SJ.; ''GABAA receptors: properties and trafficking.''; PubMed Europe PMC


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101214view11:11, 1 November 2018ReactomeTeamreactome version 66
100752view20:36, 31 October 2018ReactomeTeamreactome version 65
100296view19:13, 31 October 2018ReactomeTeamreactome version 64
99842view15:57, 31 October 2018ReactomeTeamreactome version 63
99399view14:34, 31 October 2018ReactomeTeamreactome version 62 (2nd attempt)
94502view09:18, 14 September 2017Mkutmonreactome version 61
86651view09:23, 11 July 2016ReactomeTeamreactome version 56
83166view10:15, 18 November 2015ReactomeTeamVersion54
81530view13:04, 21 August 2015ReactomeTeamVersion53
77001view08:29, 17 July 2014ReactomeTeamFixed remaining interactions
76706view12:07, 16 July 2014ReactomeTeamFixed remaining interactions
76032view10:09, 11 June 2014ReactomeTeamRe-fixing comment source
75741view11:22, 10 June 2014ReactomeTeamReactome 48 Update
75091view14:04, 8 May 2014AnweshaFixing comment source for displaying WikiPathways description
74738view08:49, 30 April 2014ReactomeTeamNew pathway

External references


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NameTypeDatabase referenceComment
5HT MetaboliteCHEBI:28790 (ChEBI)

binding and

downstream events
PathwayR-HSA-181431 (Reactome) Acetylcholine is the neurotransmitter found at neuromuscular junctions, synapses in the ganglia of the visceral motor system, and at a variety of sites within the central nervous system. A great deal is known about the function of cholinergic transmission at the neuromuscular junction and at ganglionic synapses, the actions of ACh in the central nervous system are not as well understood. Acetylcholine is synthesized in nerve terminals from acetyl coenzyme A (acetyl CoA) synthesized from glucose) and choline. This reaction is catalyzed by choline acetyltransferase (CAT). The presence of acetyltransferase in a neuron is thus a strong indication that ACh is used as one of its transmitters. Choline is present in plasma at a concentration of about 10 mM, and is taken up into cholinergic neurons by a high-affinity Na+/choline transporter. About 10,000 molecules of ACh are packaged into each neurotransmitter containing vesicle by a vesicular ACh transporter.
Activation of

kainate receptors upon glutamate

PathwayR-HSA-451326 (Reactome) Kainate receptors are found both in the presynaptc terminals and the postsynaptic neurons.
Kainate receptor activation could lead to either ionotropic activity (influx of Ca2+ or Na+ and K+) in the postsynaptic neuron or coupling of the receptor with G proteins in the presynaptic and the postsynaptic neurons.
Kainate receptors are tetramers made from subunits GRIK1-5 or GluR5-7 and KA1-2. Activation of kainate receptors made from GRIK1 or KA2 release Ca2+ from the intracellular stores in a G protein-dependent manner. The G protein involved in this process is sensitive to pertussis toxin.
Activation of NMDA

receptors and

postsynaptic events
PathwayR-HSA-442755 (Reactome) NMDA receptors are a subtype of ionotropic glutamate receptors that are specifically activated by a glutamate agonist N-methyl-D-aspartate (NMDA). Activation of NMDA receptors involves opening of the ion channel that allows the influx of Ca2+. NMDA receptors are central to activity dependent changes in synaptic strength and are predominantly involved in the synaptic plasticity that pertains to learning and memory. A unique feature of NMDA receptors, unlike other glutamate receptors, is the requirement for dual activation, both voltage-dependent and ligand-dependent activation. The ligand-dependent activation of NMDA receptors requires co-activation by two ligands, glutamate and glycine. However, at resting membrane potential, the pore of ligand-bound NMDA receptors is blocked by Mg2+. The voltage dependent Mg2+ block is relieved upon depolarization of the post-synaptic membrane. NMDA receptors are coincidence detectors, and are activated only if there is a simultaneous activation of both pre- and post-synaptic cell. Upon activation, NMDA receptors allow the influx of Ca2+ that initiates various molecular signaling cascades involved in the processes of learning and memory. For review, please refer to Cohen and Greenberg 2008, Hardingham and Bading 2010, and Paoletti et al. 2013.
Ca2+MetaboliteCHEBI:29108 (ChEBI)
Cl-MetaboliteCHEBI:17996 (ChEBI)
GABA receptor activationPathwayR-HSA-977443 (Reactome) 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).
GLRA1 ProteinP23415 (Uniprot-TrEMBL)
GLRA2 ProteinP23416 (Uniprot-TrEMBL)
GLRA3 ProteinO75311 (Uniprot-TrEMBL)
GLRA4 ProteinQ5JXX5 (Uniprot-TrEMBL)
GLRA:GLRB:GlyComplexR-HSA-975385 (Reactome)
GLRB ProteinP48167 (Uniprot-TrEMBL)
Glutamate binding,

activation of AMPA receptors and

synaptic plasticity
PathwayR-HSA-399721 (Reactome) Excitatory synaptic transmission in the brain is carried out by glutamate receptors through the activation of both ionotropic and metabotropic receptors. Ionotropic glutamate receptors are of three subtypes based on distinct physiologic properties and their differential binding of exogenous ligands namely NMDA (N-methyl D-aspartate), AMPA (alpha-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid) and Kainate . The ionotropic receptors are glutamate gated ion channels that initiate signaling by influx of ions, and are comprised of subunits with distinct structures and distinguished based on their agonist binding. Even though all three types of receptors are found at the glutamatergic synapses yet they exhibit great diversity in the synaptic distribution. The metabotropic glutamate receptors are a family of G-protein coupled receptors that are slow acting. Fast excitatory synaptic transmission is carried out through AMPA receptors. Post-synaptic transmission involves binding of the ligand such as glutamate/AMPA to the AMPA receptor resulting in the Na influx which causes depolarization of the membrane. NMDA receptors are blocked by Mg at resting membrane potential. NMDA receptors are activated upon coincident depolarization and glutamate binding are activated following AMPA receptor activation.NMDA receptors are blocked by Mg at resting
membrane potential. NMDA receptors are Ca permeable and their activity leads to increase in Ca which, leads to upregulation of AMPA receptors at the synapse which causes the long lasting excitatory post-synaptic potential (EPSP) which forms the basis of long term potentiation (LTP). LTP is one form of synaptic plasticity wherein the strength of the synapses is enhanced by either change in the number, increase in the efficacy by phosphorylation or change in the type of receptors. Phosphorylation of AMPA receptors changes the localization of the receptors, increases the single channel conductance, and increases the probability of open channel. GluR1 has four phosphorylation sites; serine 818 (S818) is phosphorylated by PKC and is necessary for LTP, serine 831 (S831) is phosphorylated by CaMKII that increases the delivery of receptors to the synapse and also increased their single channel conductance, threonine (T840) is implicated in LTP. Serine 845 (S845) is phosphorylated by PKA which regulates open channel probability. Long term depression is another form of plasticity wherein the number of AMPA receptors is diminished by either phosphorylation of GluR2 at Ser880 or dephosphorylation of GluR1 by protein phosphatase1, protein phosphatase 2A and protein phosphatase 2B (calcineurin).
Gly MetaboliteCHEBI:57305 (ChEBI)
HTR3 pentamer:5HTComplexR-HSA-975348 (Reactome)
HTR3A ProteinP46098 (Uniprot-TrEMBL)
HTR3B ProteinO95264 (Uniprot-TrEMBL)
HTR3C ProteinQ8WXA8 (Uniprot-TrEMBL)
HTR3D ProteinQ70Z44 (Uniprot-TrEMBL)
HTR3E ProteinA5X5Y0 (Uniprot-TrEMBL)
K+MetaboliteCHEBI:29103 (ChEBI)
Na+MetaboliteCHEBI:29101 (ChEBI)

Annotated Interactions

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SourceTargetTypeDatabase referenceComment
Ca2+ArrowR-HSA-975311 (Reactome)
Ca2+R-HSA-975311 (Reactome)
Cl-ArrowR-HSA-975389 (Reactome)
Cl-R-HSA-975389 (Reactome)
GLRA:GLRB:Glymim-catalysisR-HSA-975389 (Reactome)
HTR3 pentamer:5HTmim-catalysisR-HSA-975311 (Reactome)
K+ArrowR-HSA-975311 (Reactome)
K+R-HSA-975311 (Reactome)
Na+ArrowR-HSA-975311 (Reactome)
Na+R-HSA-975311 (Reactome)
R-HSA-975311 (Reactome) The 5-hydroxytryptamine receptor (HTR3) family are members of the superfamily of ligand-gated ion channels (LGICs). Five receptors (HTR3A-E) can form a homopentamer (HTR3A) or heteropentamers (HTR3A with B, C, D or E) (Barrera et al. 2005, Niesler et al. 2007; reviews - Barnes et al. 2009, Wu et al. 2015) Although heterpentamer composition can vary between the two receptors binding, the example 2xHTR3A:3xHTR3(B-E) is shown here. Binding of the neurotransmitter 5-hydroxytryptamine (5HT, serotonin) to the HTR3 complex opens the channel, which in turn, leads to an excitatory response in neurons and is permeable to sodium, potassium, and calcium ions (Miyake et al. 1995, Davies et al. 1999).
R-HSA-975389 (Reactome) The glycine receptor (GLR) is a ligand-gated ion channel. It is functional as a heteropentamer, consisting of alpha (GLRA) and beta (GLRB) subunits. With no ligand bound, the receptor complex is closed to chloride ions. Binding of the inhibitory neurotransmitter glycine (Gly) to this receptor complex increases chloride conductance into neurons and thus produces hyperpolarization (inhibition of neuronal firing) (Grenningloh et al. 1990, Nikolic et al. 1998, Handford et al. 1996).
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