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1. Neurotransmitters listed
2. Botulinum toxin
9. Black widow spider venom
Serotonin Pathways in the brain; Synapses
The principal centers for serotonergic neurones are the rostral and caudal raphe nuclei. From the rostral raphe nuclei axons ascend to the cerebral cortex, limbic regions and specifically to the basal ganglia. Serotonergic nuclei in the brain stem give rise to descending axons, some of which terminate in the medulla, while others descend the spinal cord.
Neurotransmitters are important because a lot of drugs affect neurotransmitters--block or potentiate.
Not usually a one way synaptic event--usually a circuit with excitatory and inhibitory Steps along the way to regulate neurotransmitter release
Slow: time scale of many seconds
Fast: millisecond time scale
THere are auto receptors that regulate the release of its own neurotransmitter. There are also reuptake transporters.
Sequence of events in excitatory (and inhibitory) transmission:
1. action potential propagation
2. Presynaptic depolarization
3. Ca++ entry
4. Vesicular release
5. Neurotransmitter diffusion
6. Receptor activation
Criteria for a neurotransmitter candidate:
1. Must be synthesized in the nerve
2. Must be released by the nerve following nerve stimulation (can be measured)
3. The neurotransmitter action must be mimicked by exogenous application of the neurotransmitter (nerve stimulation and exogenous application produce the same effect)
4. Exogenous application of the neurotransmitter and nerve stimulation must be blocked by the same antagonist
Hard to fulfill in CNS: hard to find a single nerve to stimulate
Synaptic Vesicle Docking; Release & Recycling
Neurotransmitter release from synaptic vesicles is activated by Ca2+ influx through voltage-gated Ca2+ channels triggered by membrane depolarization (usually requires an action potential). However, before transmitter can be released through the fusion pore, vesicles must first dock at the
presynaptic active zone and be "primed" for release. Priming involves full engagement of the ternary SNARE complex. However, fusion pore formation and full fusion to release transmitter is held in check by Ca2+ sensing proteins like synaptotagmin until the Ca2+ signal is triggered.
1. VAMPs (synaptobrevin)
Botulinum toxin blocks vesicular release
Toxins that can block transmitter release by synaptic vesicles: Botox
Clostridiumsp., toxins Clostridia are anaeobicbacteria that produce toxins acting as proteolytic enzymesthat degrade specific proteins involved in transmitter release. Cause lethal botulism and tetanus poisoning,
but also are finding a range of therapeutic use (ie., BoTox) in disorders with muscle spasticity (dystonia).
Clostridia toxins, botulinumtoxins
(serotypes A-G) and tetanus toxin are
proteins consisting of a H-chain (heavy)
and L-chain (light) connected by a
The H-chainmediates nerve terminal
plasma membrane binding, leads to toxin
internalization and translocation of the Lchain
into the cytoplasm.
Once in the cytoplasm, the L-chains are
zinc dependent endoproteases that cleave
docking / fusion proteins to disrupt the
ternary SNARE complex in docking or
linkage of the vesicle to the plasma
Botulinum is a proteolytic enzyme that breaks down SNARE proteins!
Works for a duration until the SNARE proteins can be made again before vesicular release can resume. Paralysis due to no transmission
Types of Neurotransmitters
Acetylcholine (in NMJ, autonomic ganglia, CNS)
B. Biogenic amines
3. epinephrine (released from adrenal gland--acts more like a hormone. Quasi neurotransmitter)
C. Amino acids
1. glutamate--Major excitatory amino acid in brain
2. GABA--Major inhibitory neurotransmitter in brain
3. glycine--Major inhibitory neurotransmitter--esp in spinal cord--ex. Strychnine--blocks inhibition--over excitation
D. Opioid peptides (Released endogenously to act on opiate receptors)
1. Substance P
2. VIP (vasoactive intestinal peptide)
3. endocannabinoids (retrograde transmission)
Categories of Neurotransmitters and Synaptic Transmission
Fast transmission (EPSP, IPSP): glutamate, ACh, GABA, glycine
Slow Transmission (EPSP): biogenic amines and peptides--almost all are slow
Ligand-gated channels are ionotropic (for FAST). Ligand gates. 6 transmembrane rings: 4-5 together to form a pore. Neurotransmitter binds and it opens (nicotinic receptor)
Metabotropic use intracellular second messengers (GPCR) and are SLOW. G proteinc oupled receptor. Neurotransmitter binds outside. Coupled to cyclic AMP. 7 transmembrane segements.
Some K channels are open all the time: hyperpolarize the cell--a break. If turn off then you get excitation (ex. muscarinic receptor)
BOTH fast & slow: glutamate, ACh, GABA. Fast ACh for nicotinic and slow is muscarinic
A single neurotransmitter can:
1. act as both fast and slow neurotransmitters
2. act on different receptor subtypes on the same cell
3. act on different receptor subtypes on different cells
Mechanisms that regulate neurotransmission (ACh example)
Synthesis: Acetyl CoA +choline --> ACh + CoA using choline acetyltransferase. Rate limiting step: availability of choline. Choline is pumped into terminal. Hemicholinium blocks the pump. Can't synthesize ACh
Botulinum acts on SNAPs (SNARE)
Degradation: ACh to choline + acetate with acetylcholinesterase
Once released and acts on receptors--it will be degraded by acetylcholine esterase. Makes choline available for reuptake. Ach esterase inhibitors: for Alzheimer's--allows more Ach. Not enough normally--needed for cognition/memory
Clinically used to treat alzheimer's--not super effective.
Mustard gas: very postent AChE inhibitor--too much Ach causes paralysis due to constant stimulation. Regulating Ach can be good or very bad
Mechanisms that regulate neurotransmission! (ACh)
Drugs that regulate neurotransmission
a) agonists (nicotine, muscarine)--naturally occuring
b) synthesis blockers (hemicholinium)
c) release blockers (botulinum toxin)
d) releaser (black widow spider venum)--Releases Ach--paralyze pray because massive Ach causes paralysis
e) receptor antagonist (curare, atropine)--Curare=nicotinic in south american darts and atropine=muscarinic)
f) metabolic inhibitor (physostigmine,
cholinesterase inhibitor)--Physostigmine--metabolic AChE inhibitor
Which of these drugs could have an anticholinergic effect:
Hemicholinium, Botulinum toxin,
Black widow--too much Ach causes a block in transmission eventually)
Norepinephrine as a neurotransmitter
Steps available for pharmacological
modification (simplified from text)
2.depletion of stores
3. false neurotransmitters
4. release block/inhibition
5. postsynaptic receptor antagonist
6. blocks reuptake
7. displaces NE from cytoplasmic stores
8. MAO (monoamine oxidase) inhibitors
clinically very important
10. presynaptic inhibition
Synthesized: dopamine is precursor. Taken to vesicle. Reserpine blocks uptake into vesicles (not used clinically)--depletes nerve terminal.
once in vesicle--is released to act on receptors (G protein coupled receptor to make cAMP in this case). NE only acts on GPCR. In nerve terminal--not metabolized in the cleft. Taken back up into nerve terminal instead! Important: rate limiting step in the synthesis of NE. Cocaine blocks this!! (In Ach: was availability of choline)
NE in terminal--can be metabolized by MAO, etc. or can be quickly added to vesicles.
Presynaptic inhibition: NE released and acts back on alpha 2 receptors. NE acts on own terminal to inhibit release.
Review Autonomic Nervous System
2 neuron system
Preganglionic neuron in spinal cord and postganglionic and autonomic ganglion some where
Know neurotransmitters and receptors involved.
Brief overview to autonomic neurotransmitter receptor classification
A. Cholinergic (acetylcholine is the neurotransmitter)
1. Nicotinic receptors - ionotropic: skeletal muscle, autonomic ganglia, CNS
2. Muscarinic receptors - metabotropic: smooth muscle, cardiac muscle, glands, CNS (cognition & memory). Responsible for vagal tone of the heart
B. Adrenergic (norepinephrine is the primary neurotransmitter)
1. Alpha () adrenergic receptors - metabotropic: alpha1 (postsynaptic)--blood vessels, many organs and alpha 2 (presynaptic in CNS)
2. Beta () adrenergic receptors - metabotropic: Beta 1: heart and Beta 2: bronchiole, blood vessels
C. Peptidergic (numerous) - metabotropic. Don't worry about it--mostly in gut!
Preganglionic and Postganglionic Neurotransmitters
Sympathetic NS as an example:
Normal is acetylcholine from preganglionic and norepinephrine from postganglionic (synapse on arrector pili muscle, blood vessels in skin & skeletal muscle)
Last 2 are exceptions to the rule! All other times NE is what is released from the postganglionic! Postganglionic neuron for sweat glands releases ACh!!
Ach Causes blood vessel dilation (from postganglionic)--want muscles to work well in fight/flight! (NE--constriction)
Parasympathetic:Ach released at both
Pre is long and Post is short
When Ach from pre acts on nicotinic receptors (in ganglia)---upon release from post it acts on muscarinic receptors in organ
Sympathetic: Pre is short. Post is long. Usually Ach for pre (acts on nicotinic receptors in ganglia) and NE for post
Sympathetic for sweat glands:Exception! Both Ach. Again nicotinic in ganglia and muscarinic at gland!
Adrenal medulla---modified autonomic. Ach released in adrenal medulla for nicotinic receptors to cause NE release---blood glucose metabolism effects, etc
A. alpha-adrenergic receptors
a) three subtypes are known to exits
b) located postsynaptically on blood vessels, spleen, peripheral tissues
norepinephrine (NE>EPI) on alpha 1 receptors--restrict blood vessels!
2. alpha 2-receptors
a) three subtypes are known to exits
b) located on presynaptic nerve terminals in CNS
B. beta-adrenergic receptors
a) high density in the heart and cerebral cortex
a) high density in the lung
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