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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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 (ChAT). 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.
Nicotinic acetylcholine receptors (nAchR) are ionotropic receptors that can be activated by nicotine and permeable to of monovalent (sodium, potassium) and divalent cations(calcium), however, the permeability of sodium and/or calcium maybe high or low depending on the subunit composition of the receptor. Nicotinic acetylcholine receptors are expressed widely in the central and peripheral nervous system in the presynaptic terminal, terminal bouton and post synaptic neuron. Functionally nicotinic acetylcholine receptors in the pre synaptic and postsynaptic terminals behave similarly. Nicotinic AChR are a family of acetylcholine gated pentameric receptors that are formed by the association of various combinations of mostly alpha, beta subunits (for the neuronal type) and together with gamma, delta and epsilon subunits (for the muscle type). In addition, receptors may be more diverse due the fact that some receptors have same subunits but the stoichiometry of the subunits is different.
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.
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, Traynelis et al. 2010, and Paoletti et al. 2013.
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).
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).
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). Binding of the neurotransmitter 5-hydroxytryptamine (5HT, serotonin) to the HTR3 pentamer opens the channel making it permeable to sodium, potassium, and calcium ions, which in turn leads to an excitatory response in neurons (Miyake et al. 1995, Davies et al. 1999).
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). Binding of the neurotransmitter 5-hydroxytryptamine (5HT, serotonin) to the HTR3 pentamer opens the channel making it permeable to sodium, potassium, and calcium ions, which in turn leads to an excitatory response in neurons (Miyake et al. 1995, Davies et al. 1999).
Binding of NBEA to GLRB (glycine receptor beta subunit) was demonstrated by co-immunoprecipitation of recombinant rat Glrb with endogenous Nbea from rat brain, as well as co-immunoprecipitation of recombinant rat Glrb with recombinant mouse Nbea. It was also shown, by immunocytochemistry, that NBEA and glycine receptor co-localize at postsynaptic densities of inhibitory synapses (del Pino et al. 2011). NBEA may be involved in trafficking of glycine receptors to the plasma membrane. As glycine receptors are pre-assembled at the endoplasmic reticulum (Griffon et al. 1999), the reaction diagram depicts binding of NBEA to this pre-assembled receptor complex, consisting of glycine receptor alpha and beta subunits.
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).
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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binding and
downstream eventsNicotinic acetylcholine receptors (nAchR) are ionotropic receptors that can be activated by nicotine and permeable to of monovalent (sodium, potassium) and divalent cations(calcium), however, the permeability of sodium and/or calcium maybe high or low depending on the subunit composition of the receptor. Nicotinic acetylcholine receptors are expressed widely in the central and peripheral nervous system in the presynaptic terminal, terminal bouton and post synaptic neuron. Functionally nicotinic acetylcholine receptors in the pre synaptic and postsynaptic terminals behave similarly. Nicotinic AChR are a family of acetylcholine gated pentameric receptors that are formed by the association of various combinations of mostly alpha, beta subunits (for the neuronal type) and together with gamma, delta and epsilon subunits (for the muscle type). In addition, receptors may be more diverse due the fact that some receptors have same subunits but the stoichiometry of the subunits is different.
kainate receptors upon glutamate
bindingKainate 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.
receptors and
postsynaptic eventsactivation of AMPA receptors and
synaptic plasticitymembrane 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).
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