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Neurotransmitters, Neurotransmitter receptors and their effects

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Title: Neurotransmitters, Neurotransmitter receptors and their effects


1
Neurotransmitters, Neurotransmitter receptors and
their effects
Were 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!
2
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
Ca2
3
NTS Action
  • NT diffuses across synaptic cleft to bind to
    receptor (LGC) on postsynaptic membrane
  • Can generate an electric signal there (EPSPs or
    IPSPs)?
  • 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?

4
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

5
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 aas
    long)?
  • Met-enkephalin, vasopressin (ADH), many others

www.brainexplorer.org/neurological_control/Neurolo
gical_Neurotransmitters.shtml
6
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/c
holinergic.html
7
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

8
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
    receptorsuse benzodiazepines during ethanol
    detox.
  • Glycine- also inhibitory
  • Mostly in spinal cord and brainstem motor neurons

http//pharma1.med.osaka-u.ac.jp/textbook/Anticonv
ulsants/GABA-syp.jpg
9
Catecholamines
Phenylalanine hydroxylase
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 MAOIs!

10
DISORDER OF PHENYLALANINE METABOLISMPhenylketonur
ia (PKU)?
  • A genetic, autosomal recessive disorder (120,000
    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
    aas 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/conditionphenylketonuria

11
Dopamine
  • Parkinsons 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
12
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

13
(No Transcript)
14
Ionotropic Receptors
  • Nicotinic AChR
  • Serotonin Glutamate
  • GABAA
  • Glycine

15
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

16
MajorIntracellularTransductionPathwaysUsed by
metabotropic receptors
Signaling molecule
Cell surface receptor
G protein
Effector protein
Late effectors
Target protein
cAMP Pathway
IP3 Pathway
17
Signaling by GPCRs
18
  • Adenylate cyclase and guanylate cyclase
  • Make cyclic AMP and cyclic GMP

19
Protein kinase A dissociates when activated by
cAMP
Regulatory subunit
Catalytic subunit
  • - Add/remove phosphates to/from enzymes to
    activate or deactivate them

20
Phosphatases remove phosphorylation kinases add
Better to think in terms of changes in activity
rather than activation (i.e. always basal state
of activation)?
21
  • adrenergic
  • receptor mechanism

PKA
22
Inositol Trisphosphate DAG
23
Aspects of IP3 signaling
24
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

25
Drugs and Toxins
  • Spastic paralysis vs. flaccid paralysis

26
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

27
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

28
mACH-R blocker/ competitor
  • Atropine
  • Flaccid paralysis
  • Smooth muscle, heart, and glands

29
nACH-R blocker/ competitor
  • Curare
  • From tree sap
  • Causes flaccid paralysis
  • Large dose asphyxiation

30
AchE Blockers
  • Neostigmine
  • Physostigmine
  • Spastic paralysis
  • Myasthenia Gravis-ptosis

31
AchE irreversible inhibitor
  • DFP- di-isopropyl fluorophosphates
  • Sarin
  • Spastic paralysis
  • Ventilator until AchE turnover

32
Inhibitory Neuron Blockers
  • Tetanus exotoxin
  • Blocks release of inhibitory neurotransmitters
  • Muscles cant relax
  • Spastic paralysis
  • Opposing flexor and extensor muscles contract

33
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
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