Lecture 1_neurotransmission, transmitters, and receptors PDF

Biochemistry of Neurotransmitters MDSC2402 October 2024 Lecturer: Anushka Ramjag Anushka Ramjag Anushka Ramjag Anushka Ramjag Anushka Ramjag Course Objectives Anushka Ramjag Anushka Ramjag Anushka Ramjag Anushka Ramjag Describe the struct...

Biochemistry of Neurotransmitters MDSC2402 October 2024 Lecturer: Anushka Ramjag Anushka Ramjag Anushka Ramjag Anushka Ramjag Anushka Ramjag Course Objectives Anushka Ramjag Anushka Ramjag Anushka Ramjag Anushka Ramjag Describe the structure and function of: acetylcholine, adrenaline, Neurotransmitters noradrenaline, serotonin, dopamine, histamine, glutamate, GABA, Anushka Ramjag Anushka Ramjag Anushka Ramjag Anushka Ramjag aspartate, and glycine Agonists and List examples of agonists and antagonists of the above neurotransmitters Antagonists Anushka Ramjag Receptors Anushka Ramjag Give an account Anushka of the structures Ramjag of the receptors Anushka of neurotransmitters and Ramjag how they work Discuss the involvement of neurotransmitters and their receptors in the Anushka Ramjag Disease Anushka Ramjag Anushka Ramjag Anushka Ramjag pathophysiology of neurological and psychiatric disorders such as anxiety, dementia, depression, schizophrenia, Parkinson’s disease, and migraine Discuss how the actions of the neurotransmitters in the CNS could be Treatment influenced pharmacologically to treat these disorders Anushka Ramjag Anushka Ramjag Anushka Ramjag Anushka Ramjag 01 Neurotransmission Anushka Ramjag Anushka Ramjag Anushka Ramjag Anushka Ramjag The synapse Anushka Ramjag Anushka Ramjag Anushka Ramjag Anushka Ramjag point of communication between 2 neurons Anushka Ramjag Anushka Ramjag Anushka Ramjag Anushka Ramjag OR between neuron and target cell Anushka Ramjag Anushka Ramjag Anushka Ramjag Anushka Ramjag or target cell o Neuron that sends the signal e.g. muscle or gland o Multiple branches on a single axon Anushka Ramjag Anushka Ramjag Anushka Ramjag Anushka Ramjag can create multiple synaptic clefts o Contains synaptic vesicles with o Neuron or target cell that receives the signal neurotransmitter o Can receive multiple synaptic inputs from multiple pre-synaptic neurons Anushka Ramjag Anushka Ramjago Anushka Ramjag Anushka Ramjag Has neuroreceptors o Neurotransmitters bind and trigger response Anushka Ramjag Anushka Ramjag Anushka Ramjag Anushka Ramjag Chemical and Electrical synapses Anushka Ramjag Two main Anushka types depending on mode Ramjag Anushka Ramjag Anushka Ramjag of signal transmission Chemical o Anushkao Ramjag Most commonAnushka Ramjag Anushka Ramjag Anushka Ramjag o Involve release of neurotransmitters from pre-synaptic neuron o Bind receptors on post-synaptic neuron Uni-directional Anushkaoo Ramjag Anushka Ramjag Anushka Ramjag Excitatory or inhibitory Anushka Ramjag Electrical o Anushkao Ramjag Direct electricalAnushka communication Ramjag Anushka between neurons Ramjag through gap Anushka Ramjag junctions o Allow ions to flow directly between cells o Faster transmission, bi-directional Anushkao Ramjag Anushka Less flexible: lack Ramjag capacity for signal Anushka Ramjag modulation Anushka Ramjag Anushka Ramjag Anushka Ramjag Anushka Ramjag Anushka Ramjag Chemical synaptic Anushka Ramjag Anushka Ramjag Anushka Ramjag Anushka Ramjag transmission Anushka Ramjag Anushka Ramjag Anushka Ramjag Anushka Ramjag Anushka Ramjag Anushka Ramjag Anushka Ramjag Anushka Ramjag Anushka Ramjag Anushka Ramjag Anushka Ramjag Anushka Ramjag Anushka Ramjag Anushka Ramjag Anushka Ramjag Anushka Ramjag Anushka Ramjag Anushka Ramjag Anushka Ramjag Anushka Ramjag SNARES Anushka Ramjag o Two lipid bilayers willAnushka not readily fuseRamjag Anushka in aqueous solution Ramjagconditions under physiological Anushka Ramjag Soluble N-ethylmaleimide-sensitive factor attachment protein receptors (SNAREs) help overcome o energy barriers and are responsible for nearly all fusion events in eukaryotic secretory pathways Anushka Ramjag Anushka Ramjag Anushka Ramjag Anushka Ramjag o V-SNAREs o Vesicle membrane: synaptobrevin o T-SNAREs Anushka Ramjag Anushka o Target membrane Ramjagmembrane): (i.e. pre-synaptic Anushka Ramjag syntaxin, Anushka Ramjag SNAP-25 (Synaptosomal- Associated Protein, 25kDa) o Mediate docking and exocytosis of synaptic vesicles Anushka Ramjag Anushka Ramjag Anushka Ramjag Anushka Ramjag Other molecules then disassemble and recycle vesicles and SNARE proteins to be used again o o NSF (N-ethylmaleimide Sensitive Fusion protein): ATPase that unwinds SNARE proteins to disassemble SNARE complex Anushka Ramjag Anushka Ramjag Anushka Ramjag Anushka Ramjag o SNAPs (Soluble NSF Attachment Proteins): adaptor proteins that bind to SNARE complex and help recruit NSF Anushka Ramjag Anushka Ramjag Anushka Ramjag Anushka Ramjag Anushka Ramjag Anushka Ramjag Anushka Ramjag Anushka Ramjag Anushka Ramjag Anushka Ramjag Anushka Ramjag Anushka Ramjag Anushka Ramjag Anushka Ramjag Anushka Ramjag Anushka Ramjag Anushka Ramjag Anushka Ramjag Anushka Ramjag Anushka Ramjag Excitatory vs Inhibitory post-synaptic responses Anushka Ramjag Anushka Ramjag Anushka Ramjag Anushka Ramjag Different ions can enter post-synaptic membrane (PSM) depending on type of receptor: Anushka Ramjag o Excitatory Anushka Ramjag Anushka Ramjag Anushka Ramjag oNa+ o Depolarization of PSM (inside becomes more positive) Anushka oRamjag Excitatory post-synaptic Anushka Ramjagpotential (EPSP) Anushka Ramjag Anushka Ramjag o Increased likelihood of action potential firing o Inhibitory Anushka Ramjag Anushka Ramjag Anushka Ramjag Anushka Ramjag oCl- enter o K+ can exit o Hyperpolarization of PSM (inside becomes more negative) Anushka oRamjag Anushka Ramjag Inhibitory post-synaptic Anushka Ramjag potential (IPSP) Anushka Ramjag o Reduced likelihood of continued action potential Anushka Ramjag Anushka Ramjag Anushka Ramjag Anushka Ramjag o Movement of ions cause temporary change produce a localized change in the membrane Anushka Ramjag Anushka Ramjag Anushka Ramjag potential—voltage acrossAnushka Ramjag the membrane—of the receiving cell o EPSP makes inside the cell more positive, Anushka Ramjag Anushka Ramjag Anushka Ramjag Anushka Ramjag bringing membrane potential closer to threshold for firing action potential Anushka Ramjag Anushka Ramjag Anushka o IPSP keeps Ramjag Anushka membrane potential Ramjag below the threshold Anushka Ramjag Anushka Ramjag Anushka Ramjag Anushka Ramjag o Small EPSPs or IPSPs can temporally or spatially summate to create big enough changes in polarization to have excitatory or inhibitory effect Anushka Ramjag Anushka Ramjag Anushka Ramjag Anushka Ramjag Anushka Ramjag Anushka Ramjag Anushka Ramjag Anushka Ramjag Chemical synapses are flexible Anushka Ramjag Anushka Ramjag Anushka Ramjag Anushka Ramjag o Action potential is an all-or-nothing response o Synaptic signaling is flexible Anushka Ramjag Anushka Ramjag Anushka Ramjag Anushka Ramjag o Pre-synaptic neurons can change the amount of neurotransmitter it releases o Post-synaptic neuron or target cell can change the number of receptors Anushka Ramjag Anushka Ramjag Anushka Ramjag Anushka Ramjag o These changes can strengthen or weaken nervous transmission at a particular synapse Anushka Ramjag Anushka Ramjag Anushka Ramjag Anushka Ramjag o Synaptic plasticity plays key roles in learning and memory (and addiction L) o Different pre- and post- synaptic neurons produce different neurotransmitters Anushka Ramjag Anushka Ramjag Anushka Ramjag Anushka and neuroreceptors Ramjag o Different interactions and effects 02 Neurotransmitters Anushka Ramjag Anushka Ramjag Anushka Ramjag Anushka Ramjag Classification of neurotransmitters Anushka Ramjag o Small molecule Anushka Ramjag Anushka Ramjag Anushka Ramjag 1. Amino acids o Glutamate, aspartate, GABA (γ-aminobutyric acid; not found in proteins), Anushka Ramjagglycine, taurine Anushka Ramjag Anushka Ramjag Anushka Ramjag 2. Biogenic amines: made from amino acid precursors o Dopamine, Norepinephrine, Epinephrine, Serotonin, histamine 3. Acetylcholine Anushka Ramjag Anushka Ramjag Anushka Ramjag Anushka Ramjag Neuropeptides o o made up of three or more amino acids Anushka Ramjag Anushka o larger than the Ramjag small molecule transmittersAnushka Ramjag Anushka Ramjag o >50 types e.g. endorphins Anushka Ramjag Anushka Ramjag Anushka Ramjag Anushka Ramjag Anushka Ramjag Anushka Ramjag Anushka Ramjag Anushka Ramjag Neurotoxins Anushka Ramjag Anushka Ramjag Anushka Ramjag Anushka Ramjag o Promote neurotransmitter release o α-Latrotoxin (produced by black widow spiders) forms pores in pre-synaptic membrane o Ca2+ influx causes massive release of neurotransmitters Anushka Ramjag Anushka Ramjag Anushka Ramjag Anushka Ramjag oInhibit neurotransmitter release Anushka Ramjag produced o Batrachotoxin Anushka Ramjag by certain beetles, birds,Anushka Ramjag and *frogs destroys synapticAnushka vesicles Ramjag o Irreversibly binds to Na+ channels inhibiting them from closing (neuron can no longer send signals) o Paralysis Anushka Ramjag Anushka Ramjag Anushka Ramjag Anushka Ramjag o tetanus toxin damages synaptobrevin botulinum toxins damage T-SNARES and V-SNARES o Inhibits release Anushka oRamjag of Ach Anushka Ramjag Anushka Ramjag Anushka Ramjag o Paralysis and botulism Anushka Ramjag Anushka Ramjag Anushka Ramjag Anushka Ramjag Botox Anushka Ramjag Anushka Ramjag Anushka Ramjag Anushka Ramjag Derived from botulinum toxin o o most lethal toxin known Anushka Ramjag o Blocks Anushka ACh release Ramjag causing flaccid paralysisAnushka Ramjag Anushka Ramjag o weakens muscle for 3-4 months Anushka BotoxRamjag used to: Anushka Ramjag Anushka Ramjag Anushka Ramjag remove wrinkles o o treat muscle spasticity Anushka Ramjag o excessive Anushka sweating Ramjag Anushka Ramjag Anushka Ramjag o migraine Anushka Ramjag Anushka Ramjag Anushka Ramjag Anushka Ramjag Anushka Ramjag Anushka Ramjag Anushka Ramjag Anushka Ramjag Unconventional neurotransmitters Anushka Ramjag Anushka Ramjag Anushka Ramjag Anushka Ramjag 1. Endocannabinoids a. Mood regulation, memory, pain sensation, appetite Gasotransmitters (soluble gases such as nitric oxide, carbon monoxide) 2. a. Vasodilation, synaptic plasticity, neurotransmission modulation Anushka Ramjag Anushka 3. Purinergic signalling molecules Ramjag Anushka Ramjag Anushka Ramjag ATP: acts as an excitatory neurotransmitter and is often co-released with classical neurotransmitters Anushka Ramjag Adenosine: a Anushka Ramjag breakdown product Anushka of ATP, various Ramjag signalling roles Anushka Ramjag o Not stored in synaptic vesicles Anushka Ramjag Anushka Ramjag Anushka Ramjag Anushka Ramjag o produced on demand according to body’s needs Non-directional o o some can carry impulses from post-synaptic neuron to pre-synaptic neuron Anushka o NoRamjag receptors Anushka Ramjag Anushka Ramjag Anushka Ramjag o can diffuse directly (i.e. exocytosis not required for release) o Often modulate the release of other neurotransmitters, affecting synaptic strength and plasticity 03 Neuroreceptors Anushka Ramjag Anushka Ramjag Anushka Ramjag Anushka Ramjag Ionotropic and Metabotropic receptors Anushka Ramjag Anushka Ramjag Anushka Ramjag Anushka Ramjag Neuroreceptors are proteins and can be divided into two broad classes: Anushka Ramjag Anushka Ramjag Anushka Ramjag Anushka Ramjag o Ionotropic receptors (aka ligand-activated ion channels) o Span the membrane o Open directly in response to ligand (i.e. neurotransmitter) binding Anushka Ramjag Anushka Ramjag Anushka Ramjag Anushka Ramjag o Metabotropic receptors (aka G-protein coupled receptors= GPCRS) o Neurotransmitter binding triggers a signalling pathway Anushka Ramjag Anushka Ramjag Anushka Ramjag Anushka Ramjag o Indirectly opens or closes ion channels Anushka Ramjag Anushka Ramjag Anushka Ramjag Anushka Ramjag Anushka Ramjag Anushka Ramjag Anushka Ramjag Anushka Ramjag Ionotropic receptors (ligand-activated ion channels) Anushka Ramjag Anushka Ramjag Anushka Ramjag Anushka Ramjag o Receptor is itself a channel o Neurotransmitter binding triggers conformational Anushka Ramjag Anushka Ramjag Anushka Ramjag Anushka Ramjag change, causing channel to open o Excitatory or inhibitory effect Anushka Ramjag Anushka Ramjag Anushka Ramjag Anushka Ramjag o Dependent on type and concentration of ions that pass through Anushka Ramjag Anushka Ramjag Anushka Ramjag Anushka Ramjag o Typically produce quick physiological responses Neurotransmitter removed from synapse very o Anushka Ramjag Anushka Ramjag quicklyAnushka Ramjag via enzymatic Anushka degradation or uptake Ramjag by glial cells Anushka Ramjag Anushka Ramjag Anushka Ramjag Anushka Ramjag Metabotropic receptors Typically have 7 hydrophobic o Anushka Ramjag Anushka Ramjag Anushka Ramjag transmembrane Anushka Ramjag domains o N-terminus extracellular, C-terminus intracellular Anushka Ramjag Anushka Ramjag Anushka Ramjag Anushka Ramjag o Linked to G-proteins o Activated upon neurotransmitter binding Anushka Ramjag Anushka Ramjag Anushka Ramjag Anushka Ramjag Signaling cascade triggered o o Involves secondary messengers e.g. Anushka Ramjag o Slower Anushka Ramjag responses vs ionotropic AnushkacAMP, Ramjag Anushka Ramjag IP3, or DAG Longer-lasting effects o o Can modulate neurotransmitter release and o Signalling pathways lead to diverse cellular synaptic transmission i.e. plasticity/flexibility responses e.g. opening/closing ion channels, Anushka Ramjag Anushka Ramjag Anushka o Targets for many drugs because of involvement in RamjagandAnushka gene transcription, Ramjag protein synthesis numerous physiological processes Anushka Ramjag Anushka Ramjag Anushka Ramjag Anushka Ramjag Metabotropic receptors in memory and learning Anushka Ramjag Anushka Ramjag Anushka Ramjag Anushka Ramjag o Synaptic plasticity: ability of synapses to strengthen or weaken over time Anushka Ramjag o Crucial forAnushka learning andRamjag Anushka Ramjag Anushka memory formation Ramjag o Signal to noise ratio Anushka Ramjag o Filter outAnushka unimportantRamjag Anushka info and amplify Ramjag important Anushka signals/focus on Ramjag relevant stimuli Anushka o Ramjag Anushka High density in Ramjag Anushka Ramjag Anushka Ramjag hippocampus o Can modulate ionotropic receptors by influencing their trafficking and expression Anushka Ramjag Anushka Ramjag Anushka Ramjag Anushka Ramjag  Feature Ionotropic neuroreceptors Metabotropic neuroreceptors Anushka Structure Ramjag Anushka Ligand-gated ion channels thatRamjag form a pore inAnushka Ramjag Anushka G-protein-coupled receptors;Ramjag the cell membrane do not form an ion channel pore Mechanis Receptor changes shape upon neurotransmitter Neurotransmitter binding to receptor activates m of binding, opening the ion channel and allowing G-proteins, initiating a cascade of intracellular Anushka action Ramjag Anushka ions to flow directly Ramjag across the membrane Anushka Ramjag events involving Anushka Ramjag second messengers Rapid responses (milliseconds) due to direct ion Slower responses (seconds to minutes) since Speed flow multiple steps in signal transduction Anushka Ramjag Anushka Ramjag Anushka Ramjag Anushka Ramjag Longer-lasting effects due to their involvement in Duration Usually short-lived of effect complex signalling pathways Activation can lead to a variety of cellular Anushka Functional Ramjag Activation Anushka typically Ramjag results in immediate Anushka changes responses,Ramjag Anushka including changes Ramjag in gene expression, in membrane potential, leading to excitatory or outcome enzyme activity, or modulation of other ion inhibitory postsynaptic potentials channels Anushka Ramjag Anushka Ramjag Anushka Ramjag Anushka Ramjag Anushka Ramjag Anushka Ramjag Anushka Ramjag Anushka Ramjag Anushka Ramjag Anushka Ramjag Anushka Ramjag Anushka Ramjag Anushka Ramjag Anushka Ramjag Anushka Ramjag Anushka Ramjag Anushka Ramjag Anushka Ramjag Anushka Ramjag Anushka Ramjag Anushka Ramjag Anushka Ramjag Anushka Ramjag Anushka Ramjag The End. 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