Neurotransmitters and their Receptors

• What is a neurotransmitter?

  A chemical substance which is released from the pre-synaptic nerve terminal that acts on receptors on the target cell to relay a chemical message.

  
• Types of receptors in the body

  Receptor (physiology)

  • photoRECEPTOR
  • mechanoRECEPTOR

  Receptor (immunology)

  • T cell receptor
  • Complement receptor

  Receptor (pharmacology)

  • binding site
  • drug/toxin target
  • neurotransmitter/neurohormone
• Cellular location of receptors

  
• Types of pharmacological receptors

  
• Ligand gated ion channel families: Nicotinic receptor – like


  Pentameric – each subunit contains 4 transmembrane domains

  Specific ligand binding site

  Family includes:Nicotinic acetylcholine receptor (nAChR)

  • GABAA receptor
  • 5HT3 receptor
  • Glycine receptor

  
• Ligand gated ion channel families: Ionotropic glutamate receptors

  Tetrameric – each subunit contains 3 transmembrane domains

  Ligand binding domain acts like a clam shell when ligand binds

  Endogenous ligand – glutamate

  Family includes:

  • NMDA receptor
  • AMPA receptor
  • Kainate receptor

  
• Function of ligand-gated ion channels: Depolarisation

  • excitatory
  • cation selective
  • influx of Na+/Ca2+ and efflux of K+
  • Includes: nAChR, 5HT3, NMDA, AMPA, Kainate

  
• Function of ligand-gated ion channels: Hyperpolarisation

  • inhibitory
  • anion selective
  • influx of Cl-
  • includes: GABAA and Glycine receptor

  
• G-protein couple receptor (GPCR) families

  All GPCR’s are made up of 7 transmembrane domains

  G-proteins bind intracellularly
• Rhodopsin- like (majority)

  Ligand binding site to transmembrane domains (can be extracellular or within the membrane)

  Family includes:

  • Muscarinic acetylcholine receptor (mAChR)
  • Opioid receptors
  • Noradrenergic receptors (α and β receptors)
  • Dopaminergic receptors (D1 and D2 receptors)
  • Serotonergic receptors (Except 5HT3)
  • Neuropeptide Y receptors (Y receptors)

  
• Metabotropic glutamate receptor like

  Large n-terminus where ligand binding site is (Venus fly trap) Family includes:

  • GABAB receptor
  • Metabotropic glutamate receptor (mGluR1-8)

  
• GPCR function – second messenger system

  • Neurotransmitter binds to the receptor at the ligand binding site which leads to a conformational change in the receptor
  • The GPCR activates an associated G-protein by exchanging guanosine diphosphate (GDP) bound to the G-protein for guanosine triphosphate (GTP) causing the α subunit to dissociate from the βγ subunit
  • This leads to downstream intracellular signalling which may include activation/ inhibition of an ion channel, depending on the G-protein associated to the receptor

  
• Types of neurotransmitters and receptors

  
• Monoamine neurotransmitter: Dopamine (DA)

  Precursor for noradrenaline

  Modulatory actions via G-protein coupled receptors

  • D1 family receptors – excitatory
  • D2 family receptors – inhibitory

  Involved in movement control, emotion, reward, addiction

  
• Monoamine neurotransmitters: Noradrenaline (NA)

  Modulatory actions via G-protein coupled receptors

  • α1 and β receptors – excitatory
  • α2 receptors – inhibitory

  Involved in arousal, blood pressure regulation, mood control

  
• Monoamine neurotransmitters: Serotonin (5-HT)

  • Modulatory actions via G-protein coupled receptors except 5HT3
  • Involved in sleep, appetite, thermoregulation, pain, depression, anxiety, obsessive compulsive disorders, schizophrenia

  
• Monoamine transmission pathway

  1. Synthesised in the neuron
  2. Stored in vesicles via active transport (vesicular monoamine transporter)
  3. Released from nerve terminal by exocytosis
  4. Acts on target receptor
  5. Removed from the synaptic cleft via monoamine transporter into glial cells or pre-synaptic neuron
  6. Metabolised by MAO or COMT in glial cell or pre-synaptic neuron

  
• Monoamine metabolis: MAO – monoamine oxidase

  
  

  
  

  Location: mitochondrial membrane (cytoplasmic)

  Metabolises DA, NA, 5-HT

  MAOA and MAOB – DA

  MAOA - NA and 5-HT

  
• Monoamine metabolism: COMT – catechol-o-methyl transferase

  • Location: post-synaptic neurons and glia
  • Soluble or membrane bound forms
  • Metabolises DA and NA

  
• The 2S,3R,2D (SSRRRDD) system

  • S - Synthesis
  • S - Storage
  • R - Release
  • R - Receptors
  • R - Reuptake
  • D - Degradation
  • D - Drugs & Disease
• Dopamine (DA)

  • Monoamine
  • Location in CNS

  
• Dopaminergic pathways, role, pathology

  
• Dopamine (DA)

  
• Dopamine (DA) I

  
• Dopamine (DA) II

  
• Dopamine (DA) III

  
• Dopamine (DA) IV

  
• Dopamine (DA) V

  
• Noradrenaline

  
• Noradrenergic pathways

  Pathology

  • Low NA transmission with depression • Affects blood pressure

  
• Serotonin synthesis

  
• Serotonergic pathways

  Pathology

  • Low 5-HT transmission in depression
  • Migraine (5HT1D receptor)
  • Anxiety (5HT1A receptor)
  • Emesis (5HT3)
  • Psychosis (5HT receptors)

  
• Amino acid neurotransmitters

  Glutamate

  • Major fast excitatory transmitter
  • Inotropic receptors (ion channels) – excitatory
  • NMDA, AMPA, Kainite
  • Metabotropic receptors (G-protein coupled receptors) – inhibitory (slower)
  • mGluR1-8

  GABA (Gamma aminobutyric acid)

  • Major inhibitory transmitter
  • Inotropic receptor – inhibitory
  • GABAA • Metabotropic receptors (G-protein coupled receptors) – inhibitory
  • GABAB

  Glycine

  • Inhibitory
  • Inotropic receptors
• Glutamate synthesis, metabolism and storage

  • Synthesised in the brain from metabolism of glucose (in neuron) and glutamine (in astrocytes)
  • Glutamate is stored in synaptic vesicles which actively accumulate glutamate via the vesicular glutamate transporter (VGluT)

  
• Glutamate release and re-uptake

  • Released when pre-synaptic terminal depolarises, triggering exocytosis of synaptic vesicles
  • Glutamate diffuses into synaptic cleft and acts on post-synaptic receptors
  • Glutamate is taken up by excitatory amino acid transporters (EAAT) on pre-synaptic neuron and glial cells to reduce extracellular concentration and terminate transmission

  
• Glutamatergic pathways

  • Located in many brain pathways
  • Pyramidal neurons – major output neurons of cerebral cortex, use glutamate in projections to the striatum, thalamus, various limbic structures and areas of the brain stem
  • Parallel fibres of cerebellar cortex that project and receive information to and from Purkinjie cells of cerebellum
  • Several excitatory pathways in hippocampus - involved in learning and memory

  
• GABA synthesis, metabolism and storage


  • Synthesised from glutamate by glutamate decarboxylase (GAD)
  • Metabolised by GABA transaminase
  • Actively transported into synaptic vesicles by vesicular GABA transporter (VGAT) for storage

  
• GABA release and re-uptake

  • Released when pre-synaptic terminal depolarises, triggering exocytosis of synaptic vesicles
  • Re-uptake via GABA transporter (GAT) into the pre and postsynaptic neuron and astrocytes

  
• GABAergic pathways

  
• Acetylcholine

  • Excitatory neurotransmitter
  • PNS - acts on the pre-ganglionic sympathetic and parasympathetic neurons and at the neuromuscular junction to activate muscles
  • Functions in the CNS
  • Ionotropic receptor – nicotinic acetylcholine receptor (nAChR)
  • G-protein coupled receptor – muscarinic acetylcholine receptor (mAChR)