Transcript The Chemical Basis for Neuronal Communication

Academic Half-Day
The Chemical Basis for
Neuronal Communication
Marie-Pierre Thibeault-Eybalin, R4
November 5th, 2008
Introduction
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100 billion (1011) neurons in the brain
Up to 100,000 terminal contacts / neuron
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1016 connections between neurons / brain
Connections = Synapses
 Chemical
messenger is released at pre-synaptic
membrane of axon or dendrite terminal
 It travels across synaptic cleft
 It binds onto its receptor on post-synaptic
membrane of other neuron
 It activates effector system
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Chemical messenger may be released at nonsynaptic locations to influence distant neurons
Criteria to define chemical
messenger as neurotransmitter
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3.
Localization: A putative neurotransmitter must be
localized to the presynaptic elements of an identified
synapse and must be present also within the neuron from
which the presynaptic terminal arises.
Release: The substance must be shown to be released
from the presynaptic element upon activation of that
terminal and simultaneously with depolarization of the
parent neuron.
Identity: Application of the putative neurotransmitter to the
target cells must be shown to produce the same effects as
those produced by stimulation of the neurons in question.
Examples of
neurotransmitters
Synaptic transmission
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Fast
Variable synaptic delay from pre-synaptic
neurotransmitter release to excitation or inhibition of
post-synaptic neuron
Synaptic delay depends on complexity of transduction
mechanisms at post-synaptic membrane
Synaptic delay
Receptor
Neurotransmitter Effector system
Few msec
Ligandgated ion
channel
Small molecule
Slow Hundreds of msec G-proteincoupled
Neuropeptide
Flux of ions to generate
transmembrane electrical
potential (EPSP, IPSP ±
AP if reach threshold)
 Indirect effect on ion
channel
 Enzyme activation to
produce 2nd chemical
messenger (intracellular)
Sequence of events
Regulatory mechanisms
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To regulate amount of neurotransmitter release
Pre-synaptic receptor-mediated autoregulation
 Neurotransmitter
in synaptic cleft binds to pre-
synaptic receptor
 Inhibitory feedback mechanism
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Retrograde transmission
 2nd
chemical messenger diffuses from post-synaptic
to pre-synaptic membranes, e.g. NO
Secretory vesicles
1.
Small = Synaptic vesicles
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For small molecules
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Synthesized within vesicles, e.g. NE or uploaded by high-affinity ATPproton-coupled transporters in terminals, e.g. ACh
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Recycled
 50 nm diameter
 Cluster in active zones
2.
Large dense-cored vesicles
For neuropeptides, "built-in" in neuronal soma ± co-stored
small molecule
 Not-recycled
 75-150 nm diameter
 Found in intraneuronal locations + terminals, less numerous
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3.
Neurosecretory vesicles
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Hypothalamic neuron terminals in neurohypophysis
For neurohormones
 150-200 nm diameter
Secretory vesicles
Exocytic release
Fusion pore
Docking complex
Signal transduction
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Most receptors are transmembrane glycoproteins
Binding of neurotransmitter to receptor induces conformational
change
4 transduction mechanisms
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Ligand-gated ion channels
 G-protein-coupled receptors
 Enzymes e.g. tyrosine kinase
 Ligand-dependent regulators of nuclear transcription e.g. testosterone
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Receptors often named after family of neurotransmitters they bind
e.g. cholinergic and adrenergic receptors
Multiple subtypes based on response
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Individual neurotransmitter family members of have different potency
Rank order of potency according to EC50%
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Nicotinic ACh receptors usually excitatory
Muscarinic ACh receptors usually inhibitory
Concentration of individual neurotransmitter required to reach 50% of
maximal response expected
The same neurotransmitter may have excitatory or inhibitory
responses depending on receptor type
Structure of neurotransmitter
receptors
Ligand-gated ion channels
 Multiple subunits =
transmembrane glycoproteins
connected via intra-and extracellular loops
 Cylindrical
 Binding site in transmembrane
portion
 Conformation changes opens
gate inside channel
 Selectively pass small ions
 2 genetic families based on AA
sequence homology
 Nicotinic ACh, serotonin,
GABA, glycine
 Glutamate
G-protein-coupled receptors
 Glycoprotein chains with
multiple transmembrane
loops
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Binding site in
transmembrane or extracellular portion
3 components
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-helices
β-pleated sheets
Receptor
GTP-binding heterotrimer
Effector protein (enzyme or
ion channel)
Examples
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Rhodopsin
Odorants
Biogenic amines
Bioactive peptides
β2-adrenergic receptor
G-protein action
Examples of effector proteins
Enzyme
2nd intracellular messenger
Adenylyl cyclase
cAMP
Guanylate cyclase
cGMP
Phospholipase C
IP3 and DAG
Phospholipase A2
Members of the eicosanoid family
Receptor regulation
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Desensitization
 Reduction in receptor agonist-induced response after
seconds to minutes of stimulation mediated by
conformational changes
 Homologous
 Heterologous
Phosphorylation of intracellular portion of receptor
altering its binding affinity
Downregulation of receptor number at post-synaptic
membrane
Internalization of receptor by invagination of postsynaptic membrane
Maintenance of synaptic
environment
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To reduce or eliminate neurotransmitters in synaptic cleft
Enzymatic degradation
 ACh cleaved by acetylcholinesterase
 Neuropeptides degraded by peptidases
Transporter-mediated reuptake of small molecules (not
neuropeptides) by pre-and post-synaptic neuron or glia
(extraneuronal monoamine transport; EMT)
 NET for norepinephrine
 DAT for dopamine
 SERT for serotonin
After reuptake, neurotrasmitter either recycled or degraded
by mitochondria (MAO)
 COMT for norepinephrine
Pharmacologic modification of
synaptic transmission
Drugs may affect:
 Neurotransmitter synthesis
 Vesicular uptake and storage
 Depolarization-induced exocytosis
 Neurotransmitter receptor binding
 Termination of neurotransmitter action
 Post-synaptic effector system
Metyrosine for
pheochromocytoma
-Methyldopa
VAMT
Reserpine
MAO inhibitors
Yohimbine
Guanethidine
Cocaine
Propranolol
Synopsis of clinical points
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Many drugs function by altering chemical transmission at the
synaptic cleft.
Neuropeptides play a role in the body's response to stress.
Some drugs must traverse the plasma membrane to access
receptors.
Epinephrine is used in cardiopulmonary resuscitation and to treat
anaphylactic reactions.
The excess production of catecholamines, seen in tumors such as
pheochromocytoma, can be treated by the drug metyrosine.
Reserpine is sometimes used to treat hypertension.
Reserpine may precipitate Parkinson-like symptoms or galactorrhea,
or worsen clinical depression.
α-Methyldopa is effective for managing hypertension during
pregnancy.
The side effects of guanethidine include reduced heart rate, nasal
congestion, and orthostatic hypotension.
Propranolol is used in the management of angina pectoris,
hypertension, and congestive heart failure.
Yohimbine may be effective in treating male impotence of vascular
or psychogenic origin.
Amphetamines enhance motor performance and relieve fatigue;
these are habit-forming if used inappropriately.