neurotransmitters, neurotransmitter receptors and their effects
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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. - PowerPoint PPT PresentationTRANSCRIPT
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Neurotransmitters, Neurotransmitter receptors and
their effects
No specific chapter reading for this.....stick to the slides!
We’re talking signals and what they mean to a neuron! What happens if we block signals?
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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 by presynaptic cell for recycling
VOCC
Ca+2
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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?
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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
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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
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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
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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
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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.
• Glycine- also inhibitory• Mostly in spinal cord and
brainstem motor neurons
http://pharma1.med.osaka-u.ac.jp/textbook/Anticonvulsants/GABA-syp.jpg
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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 o-methyltransferase (COMT) degrade catecholamines
• Anti-anxiety agents- MAO-inhibitors
• DO NOT MIX SYMPATHOMIMETICS WITH MAOI’s!
phenylalaninePhenylalanine hydroxylase
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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
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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
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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
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Ionotropic Receptors Nicotinic AChR Serotonin
Glutamate GABAA
Glycine
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Metabotropic ReceptorsMetabotropic Receptors
Muscarinic Acetylcholine receptor Amanita muscaria Parasympathetic effectors stimulated Increased saliva, tears, diarrhea Antidote is atropine.
alpha and Beta-Adrenergic receptoralpha1-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
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MajorMajorIntracellularIntracellular
TransductionTransductionPathwaysPathwaysUsed by Used by
metabotropic metabotropic receptorsreceptors
cAMP PathwaycAMP Pathway IP3 PathwayIP3 Pathway
Signaling moleculeSignaling molecule
Cell surface receptor
Cell surface receptor
G proteinG protein
Effector proteinEffector protein
Late effectorsLate effectors
Second messengerSecond messengercAMP IP3/DAG
Target protein
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Signaling by GPCRs
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Adenylate cyclase and guanylate cyclase– Make cyclic AMP and cyclic GMP
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Protein kinase A dissociates
when activated by
cAMP
Regulatory subunit
Catalytic subunit- Add/remove phosphates to/from enzymes to activate or deactivate them
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Phosphatases remove phosphorylation; kinases
add
Better to think in terms of changes in activity Better to think in terms of changes in activity rather than activation (i.e. always basal state of rather than activation (i.e. always basal state of
activation)activation)
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Gs
adrenergic receptor mechanismNE
AC
GTP R
C
CR
C C
RC
C
cAMP
P
PKA
cAMP
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Inositol Trisphosphate & Inositol Trisphosphate & DAGDAG
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Release of Intracellular Calcium
PKC
Aspects of IP3
signaling
Production of IP3
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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
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Drugs and Toxins
Spastic paralysis vs. flaccid paralysis
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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
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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”
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mACH-R blocker/ competitor
• Atropine• Flaccid paralysis• Smooth muscle,
heart, and glands
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nACH-R blocker/ competitor
• Curare• From tree sap• Causes flaccid
paralysis• Large dose:
asphyxiation
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AchE Blockers• Neostigmine• Physostigmine• Spastic paralysis• Myasthenia Gravis-
ptosis
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AchE irreversible inhibitor
• DFP- di-isopropyl fluorophosphates
• Sarin• Spastic paralysis• Ventilator until AchE
turnover
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Inhibitory Neuron Blockers
• Tetanus exotoxin • Blocks release of
inhibitory neurotransmitters
• Muscles can’t relax• Spastic paralysis• Opposing flexor and
extensor muscles contract
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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