Transcript 11- neurotransmitters and receptors

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!
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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 Ca+2
(destruction, diffusion away)
VOCC
• NTS reuptake by presynaptic
cell for recycling
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NTS Action
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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
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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
• 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
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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!
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DISORDER OF PHENYLALANINE METABOLISM
Phenylketonuria (PKU)
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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?
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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 5hydroxytryptamine
(5-HT)
• SSRI’- selective serotonin
reuptake inhibitors are
anti-depressant drugs
• Ecstasy causes more
release!
• Mood elevator, “feelgood” neurotransmitter
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Ionotropic Receptors
Nicotinic AChR
Serotonin
Glutamate
GABAA
Glycine
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Metabotropic Receptors
 Muscarinic Acetylcholine receptor
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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
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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
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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
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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
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 A
GTP
P
C
C
C
R
PKA
C
C

cAMP
cAMP
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Inositol Trisphosphate & DAG
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PKC
Production of IP3
Release of
Intracellular
Calcium
Aspects of
IP3
signaling
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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
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Neostigmine
Physostigmine
Spastic paralysis
Myasthenia Gravisptosis
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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
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