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Neurotransmitters, Neurotransmitter receptors and their effects We’re talking signals and what they mean to a neuron! What happens if we block signals? No specific chapter reading for this.....stick to the slides! 1 General Sequence of Events at Chemical Synapses • NTS synthesis and storage in presynaptic cell • NTS release by exocytosis (Ca++ triggered event) • Diffusion across cleft • NTS reversibly binds to receptors (LGC) and opens gates, allowing ion diffusion • NTS removal from synapse Ca+2 (destruction, diffusion away) VOCC • NTS reuptake by presynaptic cell for recycling 2 NTS Action • • • • • • NT diffuses across synaptic cleft to bind to receptor (LGC) on postsynaptic membrane Can generate an electric signal there (EPSP’s or IPSP’s) These are graded potentials (more channels, more charge flux) Effect depends which ions are allowed to diffuse across membrane, how many and for how long. Effect depends on the selectivity of the channel. What if….. the LGC are….. – Na+ selective – K+ selective – Cl- selective What happens to the voltage on the postsynaptic cell? Is it an EPSP or an IPSP? 3 Neurotransmitters (NTs) • The substance must be present within the presynaptic neuron • Must be released in response to presynaptic depolarization, which must occur in a calcium dependent manner • Specific receptors must be present on the postsynaptic cell • NT must be removed to allow another cycle of NT release, binding and signal transmission • Removal: reuptake by presynaptic nerve or glia or degradation by specific enzymes or a combination of these 4 Small molecule neurotransmitters • Acetylcholine (ACh) – ACh (“cholinergic”) • Amino Acid Neurotransmitters – Glutamate – Aspartate – GABA – Glycine Catecholamines – Norepinephrine – Epinephrine (“adrenergics”) – Dopamine • Indoleamine – Serotonin • Imidazolamine – Histamine •Peptide Neurotransmitters (usually 3-30 aa’s long) Met-enkephalin, vasopressin (ADH), many others www.brainexplorer.org/neurological_control/Neurological_Neurotransmitters.shtml 5 Acetylcholine • Used in NMJs • Sympathetic and parasympathetic ganglia in PNS • Acetylcholine esterase (AChE) • “cholinergic” neurons have ChAT enzyme (choline acetyl transferase http://abdellab.sunderland.ac.uk/Lectures/Nurses/cholinergic.html 6 Glutamate • Very important in CNS • Nearly all excitatory neurons use it • Antagonists to Glutamate receptor help stop neuronal death after stroke • Too much- excitotoxicity due to unregulated calcium influx • Too little, leads to psychosis (delusional, paranoid, lack of contact with reality 7 GABA and • Major inhibitory neurotransmitter in CNS Decreased GABAseizures Anticonvulsants target GABA receptors or act as GABA agonists Valium- increases transmission of GABA at synapses Benzodiazepines and ethanol trigger GABA receptors……use benzodiazepines during ethanol detox. Glycine • Glycine- also inhibitory • Mostly in spinal cord and brainstem motor neurons http://pharma1.med.osaka-u.ac.jp/textbook/Anticonvulsants/GABA-syp.jpg 8 Phenylalanine hydroxylase phenylalanine Catecholamines • Derived from amino acid tyrosine - common precursor • Removed by reuptake into terminals or surrounding glial cells via sodium dependent transporter • Mono-amine oxidase (MAO) and catechol omethyltransferase (COMT) degrade catecholamines • Anti-anxiety agents- MAOinhibitors • DO NOT MIX SYMPATHOMIMETICS WITH MAOI’s! 9 DISORDER OF PHENYLALANINE METABOLISM Phenylketonuria (PKU) • • A genetic, autosomal recessive disorder (1:20,000 births) Lack of enzyme phenylalanine hydroxylase Inability to convert phenylalanine (aa) from the diet to tyrosine (aa) Accumulation of breakdown products of excess phenylalanine leads to neuronal degeneration, seizures, poor motor development and irreversible mental retardation in a developing child. Testing at birth in many states, also CA. Heel stick blood sample Prevented by dietary restriction on phenylalanine. No whole protein; source of all aa’s minus this one. At least through to adulthood, while nervous system is developing. Maternal PKU: what is it? • • http://www.ddhealthinfo.org/ggrc/doc2.asp?ParentID=5166 http://ghr.nlm.nih.gov/condition=phenylketonuria • • • • • Dopamine • Parkinson’s Disease (Parkinsonism) • Loss of dopamine from neurons in substantia nigra of midbrain • Resting tremor, “pill rolling”, bradykinesia, gait • Treat with L-dopa. (Crosses BBB) or MAO inhibitors • Side effects (hallucinations, motor) The Case of the Frozen Addicts, by Langston, J. W 11 Serotonin • Synthesized from tryptophan • Also known as 5hydroxytryptamine (5-HT) • SSRI’- selective serotonin reuptake inhibitors are anti-depressant drugs • Ecstasy causes more release! • Mood elevator, “feelgood” neurotransmitter 12 13 Ionotropic Receptors Nicotinic AChR Serotonin Glutamate GABAA Glycine 14 Metabotropic Receptors Muscarinic Acetylcholine receptor Amanita muscaria Parasympathetic effectors stimulated Increased saliva, tears, diarrhea Antidote is atropine. alpha and Beta-Adrenergic receptor alpha1-receptors: bind G protein, activate inositol triphosphate and diacylglycerol as second messengers alpha2 -receptors: bind the inhibitory G-protein, restrain the adenyl cylase system, reduce cAMP levels beta-receptors: bind adenylate cyclase-stimulating G-protein, use cAMP as second messenger. Some glutamate receptors, many, many others 15 Major Intracellular Transduction Pathways Used by metabotropic receptors Signaling molecule Cell surface receptor G protein Effector protein cAMP Second messenger IP3/D AG Late effectors Target protein cAMP Pathway IP3 Pathway 16 Signaling by GPCRs 17 Adenylate cyclase and guanylate cyclase – Make cyclic AMP and cyclic GMP 18 Protein kinase A dissociates when activated by cAMP Regulatory subunit Catalytic subunit - Add/remove phosphates to/from enzymes to 19 activate or deactivate them Phosphatases remove phosphorylation; kinases add Better to think in terms of changes in activity rather than activation (i.e. always basal state of activation) 20 adrenergic receptor mechanism NE Gs A GTP P C C C R PKA C C cAMP cAMP 21 Inositol Trisphosphate & DAG 22 PKC Production of IP3 Release of Intracellular Calcium Aspects of IP3 signaling 23 NT postsynaptic response and gene expression • Open channels • Alter gene expression • Second messenger activation can lead to phosphorylation of proteins that in turn regulate gene transcription 24 Drugs and Toxins Spastic paralysis vs. flaccid paralysis 25 Sodium VGC Blockers • Lidocaine- used as anesthesia • Tetrodotoxin-puffer fish and newts (TTX) • Saxitoxin- caused by red tide; dinoflagellate; accumulates in shellfish (SXT) • Flaccid paralysis 26 Vesicle blockers • Clostridium botulinum: • It is a protease that breaks down one of the fusion proteins (docking proteins that anchor the vesicle to the membrane) • Inhibits neurotransmitter release • Undercooked turkey; dented cans • Flaccid paralysis • “BOTOX” 27 mACH-R blocker/ competitor • Atropine • Flaccid paralysis • Smooth muscle, heart, and glands 28 nACH-R blocker/ competitor • Curare • From tree sap • Causes flaccid paralysis • Large dose: asphyxiation 29 AchE Blockers • • • • Neostigmine Physostigmine Spastic paralysis Myasthenia Gravisptosis 30 AchE irreversible inhibitor • DFP- di-isopropyl fluorophosphates • Sarin • Spastic paralysis • Ventilator until AchE turnover 31 Inhibitory Neuron Blockers • Tetanus exotoxin • Blocks release of inhibitory neurotransmitters • Muscles can’t relax • Spastic paralysis • Opposing flexor and extensor muscles contract 32 Spider Venom • Black widow: causes Ach release – Lack of inhibitory neurotransmitters – Spastic paralysis • Brazilian Wandering Spider and Viagra? – Spider venom increases NO release – Viagra blocks enzyme that degrades NO – Most venomous of all spiders/ more human deaths 33