Academic Half-Day
The Chemical Basis for Neuronal Communication
Marie-Pierre Thibeault-Eybalin, R4
November 5th, 2008
Introduction 100 billion (1011) neurons in the brain Up to 100,000 terminal contacts / neuron
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
Chemical messenger may be released at non-synaptic locations to influence distant neurons
Criteria to define chemical messenger as neurotransmitter1. 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.
2. 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.
3. 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 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
Fast Few msec Ligand-gated ion channel
Small molecule Flux of ions to generate transmembrane electrical potential (EPSP, IPSP ± AP if reach threshold)
Slow Hundreds of msec G-protein-coupled
Neuropeptide Indirect effect on ion channel Enzyme activation to produce 2nd chemical messenger (intracellular)
Sequence of events
Regulatory mechanisms
To regulate amount of neurotransmitter release Pre-synaptic receptor-mediated autoregulation
Neurotransmitter in synaptic cleft binds to pre-synaptic receptor
Inhibitory feedback mechanism Retrograde transmission
2nd chemical messenger diffuses from post-synaptic to pre-synaptic membranes, e.g. NO
Secretory vesicles1. Small = Synaptic vesicles
For small molecules Synthesized within vesicles, e.g. NE or uploaded by high-affinity ATP-
proton-coupled transporters in terminals, e.g. ACh 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
3. Neurosecretory vesicles Hypothalamic neuron terminals in neurohypophysis For neurohormones 150-200 nm diameter
Secretory vesicles
Exocytic release
Docking complex
Fusion pore
Signal transduction Most receptors are transmembrane glycoproteins Binding of neurotransmitter to receptor induces conformational
change 4 transduction mechanisms
Ligand-gated ion channels G-protein-coupled receptors Enzymes e.g. tyrosine kinase Ligand-dependent regulators of nuclear transcription e.g. testosterone
Receptors often named after family of neurotransmitters they bind e.g. cholinergic and adrenergic receptors
Multiple subtypes based on response Nicotinic ACh receptors usually excitatory Muscarinic ACh receptors usually inhibitory
Individual neurotransmitter family members of have different potency Rank order of potency according to EC50%
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 receptorsLigand-gated ion channels Multiple subunits =
transmembrane glycoproteins connected via intra-and extra-cellular 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 -helices β-pleated sheets
Binding site in transmembrane or extra-cellular portion
3 components Receptor GTP-binding heterotrimer Effector protein (enzyme or
ion channel) Examples
Rhodopsin Odorants Biogenic amines Bioactive peptides β2-adrenergic receptor
G-protein action
Examples of effector proteinsEnzyme 2nd intracellular messenger
Adenylyl cyclase cAMP
Guanylate cyclase cGMP
Phospholipase C IP3 and DAG
Phospholipase A2 Members of the eicosanoid family
Receptor regulation
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 post-synaptic membrane
Maintenance of synaptic environment 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
VAMT Reserpine
-Methyldopa
Guanethidine
Propranolol
Yohimbine
Cocaine
MAO inhibitors
Synopsis of clinical points 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.
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