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Receptors and transduction mechanisms I – MV Hejmadi How does the neuron determine which neurotransmitter (NT) to respond to? What should the response be? Neuronal communication at the synapse is mediated by the specific activation of receptors by NT. Therefore the nature of the response relies mainly on specific receptors at the post-synaptic membrane. These receptors must 1) Bind to the NT 2) Transduce a signal into the post-synaptic neuron Classical neurotransmitters (NT) bind to two classes of receptors, ionotropic and metabotropic resulting in a change in the excitability of the plasma membrane. These 2 classes of receptors differ in their structural and pharmacological properties. Ionotropic receptors (iR): The ionotropic receptors are ligand gated ion channels (LGIC), ie upon binding to a NT that has been released from presynaptic terminal, charged ions such as Na+ and Ca2+ pass through a channel in the centre of the receptor complex. This flow of ions results in a depolarisation of the plasma membrane at the post synaptic terminal and the generation of an electrical current that is propagated down the processes (dendrites and axons) of the neuron to the next in line. These receptors mediate rapid and reversible transmission due to the direct coupling of the receptor to the ion channel it gates. (Fig 11-8, Levitan). REF: Madden, D. The structure and function of glutamate receptor ion channels (2002). Nature Revs Neurosci. 3, 91. A model for iGluR activation and desensitization Upper row: ionotropic glutamate receptor (iGluR) channel physiology. In response to the application of glutamate to mouse embryonic hippocampal neurons, non-NMDA (N-methyl-D-aspartate) iGluRs open and then rapidly desensitize to a steady-state level. Middle row: schematic top view of channels in the resting, open and desensitized states. Binding of glutamate (Glu) triggers a conformational change that opens the ion pore (red lightning bolt). Although agonist remains bound, a further, most likely interdomain conformational change allows the channel to close again. Some examples of ionotropic receptors and subunits Glutamate Acetylcholine GABAA Glycine (nicotinic) AMPA NMDA Kainate GluR1 GluR2 GluR3 GluR4 NR1 NR2A NR2B NR2C NR2D GluR5 GluR6 GluR7 KA1 KA2 1-7 1-4 1-4 -3 1-10 1-4 1-4 5-hydroxy tryptamine (serotonin) 5-HT3 Glutamate receptors are tetrameric – a ‘dimer of dimers’ GABA, Acetylcholine, Glycine and 5-hydroxy tryptamine (serotonin) receptors are pentameric Metabotropic receptors (G-protein-coupled receptors, GPCR): These receptors are not directly coupled to their ion channels and transduce the signal via guanyl nucleotide-binding proteins (G-proteins) that activate intracellular second messenger pathways (Fig 12-2 Levitan). In contrast to ionotropic receptor action however, these responses are slower and longer lasting. Metabotropic receptor subunits (a few examples) Glutamate Acetycholine GABAB Dopamine (muscarininc) Class1 ClassII ClassIII mGluR1 mGluR2 mGluR4 GABABR1 D1A M1 mGluR5 mGluR3 mGluR6 GABABR2 D1B M2 mGluR7 D2 M3 M4 mGluR8 D3 M5 D4 5-HT 5-HT1 5-HT2 5-HT3 5-HT4 5-HT5 5-HT6 5-HT7 histamine H1 H2 H3 Some metabotropic receptors are dimeric (e.g. mGluR and GABABR) Receptors to the same ligand can signal through different G-proteins – ClassI mGluR increase IP3 and Ca2+ whereas ClassII mGluR reduce cAMP What are the major NT in the mammalian brain? Quantitatively, simple amino acids glutamate and GABA are the most abundant NT in the mammalian brain and mediate fast transmission in the CNS via iR. In general, although not always (during development), GABA is inhibitory whereas glutamate is excitatory on post synaptic neurons. A) L-Glutamate is the major excitatory neurotransmitter in the mammalian CNS, acting through both ligand gated ion channels (iGluRs) and metabotropic G-protein coupled receptors(mGluR). Activation of these receptors is responsible for basal excitatory synaptic transmission and many forms of synaptic plasticity such as long-term potentiation (LTP) and long-term depression (LTD), which are thought to underlie learning and memory. They are thus also potential targets for therapies for CNS disorders such as epilepsy and Alzheimer's disease. Functions: IGluRs glutamate receptors play a vital role in the mediation of excitatory post synaptic potentials (EPSPs) ie on binding glutamate that has been released from a companion cell, charged ions such as Na+ and Ca2+ pass through a channel in the centre of the receptor complex. This flow of ions results in a depolarisation of the plasma membrane and the generation of an electrical current that is propagated down the processes (dendrites and axons) of the neuron to the next in line. There are multiple Ionotropic Glutamate Receptors (iGluR) Structure: iGluRs are tetrameric (i.e. a dimer of dimers) assemblies, and are subdivided into three groups; AMPA, NMDA and Kainate receptors, based on their pharmacology. All ionotropic glutamate receptor subunits share a common basic structure. Like other ligand gated ion channels, such as the GABAA receptor, the iGluR is pentameric with each subunit possessing four hydrophobic regions within the central portion of the sequence (TMI – IV). However, in contrast to other receptor subunits, the TMII domain forms a re-entrant loop giving these receptor subunits an extracellular N-terminus and intracellular C-terminus. In addition, the long loop between TMIII and TMIV, which is intracellular in other ligand gated ion channel subunits, is exposed to the cell surface, and forms part of the binding domain with the C-terminal half of the N-terminus. (see fig below) REF: Madden, D. (2002). Nature Revs Neurosci. 3, 91. The modular nature of iGluR subunits. The amino terminus of ionotropic glutamate receptor (iGluR) subunits is extracellular. An amino-terminal domain (NTD) is followed by the S1 half-domain, two transmembrane domains with an intervening reentrant P loop, the S2 half-domain and a third transmembrane domain. The carboxyl terminus is located in the cytoplasm, where it can interact with proteins of the postsynaptic density. The S1 and S2 half-domains form the iGluR ligand-binding domain The 'dimer-of-dimers' model of iGluR assembly30. Monomers associate most strongly through interactions between their amino-terminal domains (NTDs) (star in middle figure). Dimers undergo a secondary dimerization, mediated by interactions in the S2 and/or transmembrane domains (stars in righthand figure). The crystallographically observed S1S2 dimer probably corresponds to this secondary dimerization interaction. So why have multiple iR? e.g. glutamate activates both AMPA and NMDA receptors, both of which can be found together on the same synapse. How is synaptic transmission regulated? In the case of glutamate, the strength of the stimulus controls the activation of either AMPA or NMDA receptor. There are essential differences in properties of the two receptors. The ion channel gated by NMDA is permeable to Na+, K+ and Ca2+, but most of the current is carried by Ca2+. A striking feature of the NMDA receptor is that the ion channel is blocked by extracellular Mg2+ in a voltage-dependent manner. A weak stimulus will activate the AMPA receptors only; a stronger stimulus will also activate the NMDA receptors, causing a greatly increased post-synaptic signal. This property is crucial to the role of NMDA R in certain types of synaptic plasticity. NMDAR expression is region-specific in the mammalian brain and is also developmentally regulated. B) GABA (-butyric acid) is a major CNS inhibitory neurotransmitter in the mammalian CNS GABA receptors can be divided into three classes A, B & C of GABA which GABAA and GABAC receptors are ionotropic, while ClGABAB receptors are metabotropic The GABAA receptors are found mainly in neurons, glia and adrenal medulla cells whereas GABAC receptors are found mainly in the retina The GABAA receptors are pentameric, consisting of separate subunits with an 2,2, arrangement similar to that found for neuronal nicotinic receptors. The ligand binding site is located at the interface between the and subunits. In addition to endogenous GABA, several different drugs bind to the GABAAR, which allosterically modulate the binding and kinetics of the ion channel. The benzodiazepine binding site is located at a similar level at the interface between the and subunits. Each subunit is comprised of four hydrophobic sequences which span the membrane, with a large extracellular amino terminus containing the binding site and a carboxyl terminus located intracellularly. Pharmacology distinguishes the A/C and B receptors. Fast responses are elicited by A & is mimicked by muscimol and blocked by bicuculine. B elicits slower responses that are insensitive to bicuculine and mimicked by baclofen