Lecture 13 - Scrogin - Synaptic Transmission Flashcards
List the 5 steps of synaptic transmission
- Neurotransmitter synthesis
- Vesicular storage
- Synaptic release
- Neurotransmitter binding to receptor
- Termination of neurotransmitter action
Describe neurotransmitter synthesis
Precursors need to be brought into cytosol where they can be acted upon and made into neurotransmitter
Brought into cell via facilitated transport … uses Na+ gradient
Dietary intake of amino acids can influence the availability of precursors (ex: low Trp = dec 5-HT production)
Neurotransmission can be increased at the synthesis step by ____
Precursor loading
ex: L-DOPA
What are stored in vesicles?
Almost all neurotransmitters except for gases
What is the purpose of vesicular storage?
Protection from degradative enzymes in the cytosol
*If vesicular transport is inhibited, neurotransmitters in the cytoplasm can be degraded
Synaptic release involves interaction of which proteins?
SNAREs
SNAREs can be degraded by what?
Toxins such as botulism (degrades snares on cholinergic NMJ)
*disrupts vesicle fusion with the membrane and prevents Ca2+ dependent exocytosis of NT
Describe the MOA for amphetamine/ephedrine
Indirectly acting drug that stimulates NT release (dopamine and NE) a Ca2+ independent manner
Reverses direction of NT transport (reverses monoamine reuptake transporters)
Results in the release of endogenous NT
The most selective manipulation of synaptic transmission is via drugs that _____
Bind directly to receptors (direct-acting)
What are the 3 mechanisms by which NT action can be terminated?
- Re-uptake
- Diffusion out of synaptic cleft
- Metabolic transformation/degradation
*mechanism depends on NT
List 3 potential sites of NT reuptake
- Pre-synaptic nerve terminal 2. Post-synaptic nerve cell
3. Surrounding glial cells
Tyrosine is involved in the synthesis of _____ in _____ cell types
Tyrosine is involved in the synthesis of dopamine in noradrenergic and dopaminergic neurons
What is the rate limiting enzyme for the production of catecholamines?
Tyrosine hydroxylase
*Tyr to DOPA conversion
What is Metyrosine?
Binds to Tyr Hydroxylase but doesn’t give DOPA, so it reduces NE production
*used to treat HTN
What are the beneficial and adverse effects of L-DOPA?
Beneficial –> is a dopamine precursor so used to treat Parkinson’s (dopaminergic neurons are damaged)
Adverse –> DOPA loading can negatively effect the cardiovascular system
L-DOPA to dopamine conversion is blocked by?
Carbidopa
*this is called synthesis inhibition
What is carbidopa used for?
It doesn’t cross BBB and is used to reduce cardiovascular side effects of L-DOPA in peripheral adrenergic nerves
What is VMAT and what process is it involved in?
VMAT is the vesicular monoamine transporter that carries dopamine to synaptic vesicles
Conversion of dopamine to NE takes place in this vesicle transporter (because the enzymes are also inside) so NE isn’t degraded in the cytosol
What is reserpine used to block?
Blocks VMAT which results in depletion of monoamines (dopamine, 5-HT, and NE)
Also blocks monoamine vesicular uptake in CNS because it can cross BBB
What drug can be used to reduce NT release and how does it work?
Bretylium
Inhibits excitability of nerve terminal membrane
Is selective for the NE transporter
Inhibits action potential generation and Ca2+ dependent synaptic vesicle fusion, which leads to decreased NE release
NE binds to what receptors?
Alpha and Beta Adrenergic Receptors
Adrenergic antagonists and agonists are used for treating…
CV and respiratory diseases
Mood disorders
Termination of NT (and monoamine) action is primarily mediated by which mechanism?
Re-uptake
What are COMT and MAO for?
COMT (catecholamine-o-methyltransferase) is found in interstitial tissue mediates termination of exogenous NE via metabolizing it in the plasma
MAO (monoamine oxidase) is in the cell cytoplasm and rapidly oxidases NE and dopamine in the cytoplasm that’s not transported in vesicles within time
Reuptake of monoamines is blocked/inhibited by?
Cocaine and tri-cyclic antidepressants
*SSRIs are more selective (inhibit serotonin reuptake)
Antidepressant Side Effects
They can have significant systemic side effects…particularly cardiovascular (richly innervated by noradrenergic neurons)
COMT metabolizes…
Circulating catecholamines (ex: released by adrenal or administered exogenously)
What is a drug that is resistant to degradation by COMT?
Phenylephrine (a synthetic drug that activates adrenergic receptors…is a direct adrenergic agonist)
Thus they have a longer half life
Identify the indication and mechanism of action for MAOIs (MAO inhibitors)
Result in increased catecholamines in the cytoplasm
Accumulation of NE reverses direction of the transporter protein, which leads to expulsion of NE into synapse
Anti-depressant that can give high blood pressure if there’s too much NE released
What is a contraindication with MAOIs
Tyramine (is normally subjected to 1st pass metabolism in liver by MAOs)
Tyramine accumulates if given with MAOI’s and is transported to adrenergic cells where it competes with NE for transport…results in even higher levels of cytoplasmic NE
Cytoplasmic accumulation of NE leads to….
Reversal of reuptake transporter –> Excessive release of NE –>
Hypertensive Crisis
Give an overview of neuropeptide production and release
Neuropeptides are often produced within other neuronal types and are co-released when the nerve terminal is activated
What is the issue with peptide neurotransmitters?
They can’t cross the BBB
Thus, many non-peptidergic receptor agonists/antagonists have been developed to allow it to get to CNS
Naloxone vs Naltrexone: Indications
Naloxone = small lipophilic molecule used to reverse opioid overdose
Naltrexone = has a longer duration of action and is used for treating opioid addiction and alcoholism
*They are both non-peptide blockers of opioid receptors in CNS
What is Lisinopril used for?
It’s an ACE Inhibitor (inhibits peptide cleavage of Angiotensin 1 to 2)
What are 5 monoamines?
5-HT
Histamine
Catecholamines (dopamine, NE, epi)
Neurotransmission of monoamines is typically terminated via which mechanism?
Reuptake into presynaptic cell
Glutamine actions are typically terminated by reuptake by which two mechanisms?
proteins expressed on target cells or on glial cells close to synapse
Where are degradative enzymes for monoamines located?
Floating in the intersitital fluid…so it’s a slower mechanism because the NT must diffuse away from synapse to encounter the degradative enzyme
If NE was injected to help raise blood pressure, will it be degraded slowly or rapidly?
Rapidly because interstitial fluid degradative enzymes are typically also found in the plasma
Is NO packaged in synaptic vesicles?
No, because it’s a gas and thus cannot be packaged
Therefore, it is produced when it’s needed
What does an autoreceptor do?
Bind NT that is released by the neuron on which they are expressed and can influence further neurotransmission by influencing things like how much Ca2+ is in cell to stimulate vesicular binding of synaptic membrane
Glial cells take up what neurotransmitter and why?
Majority of glutamate is taken up by glial cells to reduce cytotoxicity
Are neurotransmitters transported by only one transporter?
No, various transporters can transport the same NT
What terminates the action of ACh?
Cholinesterases
What does a choline transporter do and why?
Recycles choline back to a cholinergic cell
*Thus, you would not target this transporter to influence ACh neurotransmission
What are the indications and side effects of Reserpine?
Is an anti-hypertensive (via decreased NE), but at high doses can reduce serotonin and dopamine which leads to suicidal behavior
What are the indications of bretylium?
Is used for emergent arrhythmias and intensive care
What foods are rich in Tyramine?
sausages, fermented cheeses, and red wine
Where are peptide neurotransmitters stored?
Large Dense Core Vesicles away from the synapse (thus requires longer stimulus for release)
