Neurotransmitter receptors and postsynaptic signal transmission (Homo sapiens)

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Bibliography

1. Hardingham GE, Bading H.; ''Synaptic versus extrasynaptic NMDA receptor signalling: implications for neurodegenerative disorders.''; PubMed Europe PMC Scholia
2. Bettler B, Kaupmann K, Mosbacher J, Gassmann M.; ''Molecular structure and physiological functions of GABA(B) receptors.''; PubMed Europe PMC Scholia
3. Steinlein OK, Bertrand D.; ''Neuronal nicotinic acetylcholine receptors: from the genetic analysis to neurological diseases.''; PubMed Europe PMC Scholia
4. Kessels HW, Malinow R.; ''Synaptic AMPA receptor plasticity and behavior.''; PubMed Europe PMC Scholia
5. Jane DE, Lodge D, Collingridge GL.; ''Kainate receptors: pharmacology, function and therapeutic potential.''; PubMed Europe PMC Scholia
6. Gotti C, Clementi F, Fornari A, Gaimarri A, Guiducci S, Manfredi I, Moretti M, Pedrazzi P, Pucci L, Zoli M.; ''Structural and functional diversity of native brain neuronal nicotinic receptors.''; PubMed Europe PMC Scholia
7. 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 Scholia
8. Barnes NM, Hales TG, Lummis SC, Peters JA.; ''The 5-HT3 receptor--the relationship between structure and function.''; PubMed Europe PMC Scholia
9. 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 Scholia
10. 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 Scholia
11. Albuquerque EX, Pereira EF, Alkondon M, Rogers SW.; ''Mammalian nicotinic acetylcholine receptors: from structure to function.''; PubMed Europe PMC Scholia
12. Pinard A, Seddik R, Bettler B.; ''GABAB receptors: physiological functions and mechanisms of diversity.''; PubMed Europe PMC Scholia
13. Michels G, Moss SJ.; ''GABAA receptors: properties and trafficking.''; PubMed Europe PMC Scholia
14. Traynelis SF, Wollmuth LP, McBain CJ, Menniti FS, Vance KM, Ogden KK, Hansen KB, Yuan H, Myers SJ, Dingledine R.; ''Glutamate receptor ion channels: structure, regulation, and function.''; PubMed Europe PMC Scholia
15. Cull-Candy S, Kelly L, Farrant M.; ''Regulation of Ca2+-permeable AMPA receptors: synaptic plasticity and beyond.''; PubMed Europe PMC Scholia
16. Itier V, Bertrand D.; ''Neuronal nicotinic receptors: from protein structure to function.''; PubMed Europe PMC Scholia
17. Padgett CL, Slesinger PA.; ''GABAB receptor coupling to G-proteins and ion channels.''; PubMed Europe PMC Scholia
18. 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 Scholia
19. Paoletti P, Bellone C, Zhou Q.; ''NMDA receptor subunit diversity: impact on receptor properties, synaptic plasticity and disease.''; PubMed Europe PMC Scholia
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 Scholia
21. Cohen S, Greenberg ME.; ''Communication between the synapse and the nucleus in neuronal development, plasticity, and disease.''; PubMed Europe PMC Scholia
22. 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 Scholia
23. 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 Scholia
24. Moss SJ, Smart TG.; ''Constructing inhibitory synapses.''; PubMed Europe PMC Scholia
25. 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 Scholia
26. Lee HK.; ''Synaptic plasticity and phosphorylation.''; PubMed Europe PMC Scholia

History

External references

DataNodes

Name	Type	Database reference	Comment
5HT	Metabolite	CHEBI:28790 (ChEBI)
Acetylcholine binding and downstream events	Pathway	R-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 binding	Pathway	R-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	Pathway	R-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+	Metabolite	CHEBI:29108 (ChEBI)
Cl-	Metabolite	CHEBI:17996 (ChEBI)
GABA receptor activation	Pathway	R-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	Protein	P23415 (Uniprot-TrEMBL)
GLRA2	Protein	P23416 (Uniprot-TrEMBL)
GLRA3	Protein	O75311 (Uniprot-TrEMBL)
GLRA4	Protein	Q5JXX5 (Uniprot-TrEMBL)
GLRA:GLRB:Gly	Complex	R-HSA-975385 (Reactome)
GLRB	Protein	P48167 (Uniprot-TrEMBL)
Glutamate binding, activation of AMPA receptors and synaptic plasticity	Pathway	R-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	Metabolite	CHEBI:57305 (ChEBI)
HTR3 pentamer:5HT	Complex	R-HSA-975348 (Reactome)
HTR3A	Protein	P46098 (Uniprot-TrEMBL)
HTR3B	Protein	O95264 (Uniprot-TrEMBL)
HTR3C	Protein	Q8WXA8 (Uniprot-TrEMBL)
HTR3D	Protein	Q70Z44 (Uniprot-TrEMBL)
HTR3E	Protein	A5X5Y0 (Uniprot-TrEMBL)
K+	Metabolite	CHEBI:29103 (ChEBI)
Na+	Metabolite	CHEBI:29101 (ChEBI)

Annotated Interactions

Source	Target	Type	Database reference	Comment
	Ca2+	Arrow	R-HSA-975311 (Reactome)
Ca2+			R-HSA-975311 (Reactome)
	Cl-	Arrow	R-HSA-975389 (Reactome)
Cl-			R-HSA-975389 (Reactome)
GLRA:GLRB:Gly		mim-catalysis	R-HSA-975389 (Reactome)
HTR3 pentamer:5HT		mim-catalysis	R-HSA-975311 (Reactome)
	K+	Arrow	R-HSA-975311 (Reactome)
K+			R-HSA-975311 (Reactome)
	Na+	Arrow	R-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).