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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!. General Sequence of Events at Chemical Synapses.
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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!
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 (destruction, diffusion away) • NTS reuptake bypresynaptic cell for recycling VOCC Ca+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?
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
Catecholamines Norepinephrine Epinephrine (“adrenergics”) Dopamine Indoleamine Serotonin Imidazolamine Histamine Small molecule neurotransmitters • Acetylcholine (ACh) • ACh (“cholinergic”) • Amino Acid Neurotransmitters • Glutamate • Aspartate • GABA • Glycine • Peptide Neurotransmitters (usually 3-30 aa’s long) • Met-enkephalin, vasopressin (ADH), many others www.brainexplorer.org/neurological_control/Neurological_Neurotransmitters.shtml
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
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
Glycine- also inhibitory Mostly in spinal cord and brainstem motor neurons GABA and Glycine • Major inhibitory neurotransmitter in CNS • Decreased GABA-seizures • 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. http://pharma1.med.osaka-u.ac.jp/textbook/Anticonvulsants/GABA-syp.jpg
Phenylalanine hydroxylase Catecholamines phenylalanine • 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 o-methyltransferase (COMT) degrade catecholamines • Anti-anxiety agents- MAO-inhibitors • DO NOT MIX SYMPATHOMIMETICS WITH MAOI’s!
DISORDER OF PHENYLALANINE METABOLISMPhenylketonuria (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
Serotonin • Synthesized from tryptophan • Also known as 5-hydroxytryptamine (5-HT) • SSRI’- selective serotonin reuptake inhibitors are anti-depressant drugs • Ecstasy causes more release! • Mood elevator, “feel-good” neurotransmitter
Ionotropic Receptors • Nicotinic AChR • Serotonin Glutamate • GABAA • Glycine
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
Second messenger cAMP IP3/DAG MajorIntracellularTransductionPathwaysUsed by metabotropic receptors Signaling molecule Cell surface receptor G protein Effector protein Late effectors Target protein cAMP Pathway IP3 Pathway
Adenylate cyclase and guanylate cyclase • Make cyclic AMP and cyclic GMP
Protein kinase A dissociates when activated by cAMP Regulatory subunit Catalytic subunit - Add/remove phosphates to/from enzymes to 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)
NE C C C C GTP R R R C C cAMP • adrenergic receptor mechanism PKA
Release of Intracellular Calcium PKC Production of IP3 Aspects of IP3 signaling
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
Spastic paralysis vs. flaccid paralysis Drugs and Toxins
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
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”
mACH-R blocker/ competitor • Atropine • Flaccid paralysis • Smooth muscle, heart, and glands
nACH-R blocker/ competitor • Curare • From tree sap • Causes flaccid paralysis • Large dose: asphyxiation
AchE Blockers • Neostigmine • Physostigmine • Spastic paralysis • Myasthenia Gravis-ptosis
AchE irreversible inhibitor • DFP- di-isopropyl fluorophosphates • Sarin • Spastic paralysis • Ventilator until AchE turnover
Inhibitory Neuron Blockers • Tetanus exotoxin • Blocks release of inhibitory neurotransmitters • Muscles can’t relax • Spastic paralysis • Opposing flexor and extensor muscles contract
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