L13 concepts Flashcards
5 steps in Neurotransmission
- NT synthesis
- Vesicular Storage
- Synaptic Release
- Binding to receptor
- Termination of transmission
Requirements for NT synethesis
precursors
transport into the cell
enzymatic action
Thing that can affect NT synethesis
- therapeutic drugs can inhibit enzymes involved
- dietary intake of certain amino acids can influence availability (low tryptophan intake can reduce serotonin)
- Precursor loading- can increase neurotransmission (L-DOPA in parkinson’s disease)
which NT’s are stored in vesicles?
All except gases and some nucleosides
What are the benefits to storing NTs in vesicles
protects them from degradation by cytosolic enzymes and concentrates them for release (if storage transporters are inhibited then NTs get degraded)
Synaptic Release
Depolarization of the nerve terminal > Ca channels open and Ca influx > SNARE proteins on the vessel interact with SNARE proteins on the membrane > rapid release of NTs
Boxulinum toxin
degrades SNAREs of the cholinergic neuromuscular junction resulting in skeletal muscle paralysis. Can be used to treat muscle spasms
Endocytosed into cholinergic neurons
Degrades SNARES
Prevents calcium-dependent exocytosis of neurotransmitter
amphetamine synaptic release
has affinity for monoamine re-uptake transporters
leads to transporter phosphorylation -which reverses the direct of NT transport
probably also inhibits vesicular uptake proteins
calcium-independent release of neurotransmitter (no voltage change or Ca influx)
SNARES
Enable calcium-dependent docking of vesicle with pre-synaptic membrane
Enable exocytosis of neurotransmitter
indirect acting drugs
can increase neurotransmission and increase the effects of activating a receptor by stimulating the release of endogenous NT
receptor binding
can bind receptors on pre and post synaptic cell membranes
drugs that bind directly to receptors provide the most selective manipulation of synaptic transmission
drugs acting on pre-synaptic receptors to modulate NT release can contribute to some side effects
3 mechanisms for Termination of NT action
- reuptake (can occur at the pre-synaptic nerve terminal, the post-synaptic cell or the surrounding glial cells depending on the location of the reuptake protein)
- Diffusion (out of the synaptic cleft)
- Metabolic transformation and degradation
Dopamine is made from what precursor and by what enzyme?
Tyrosine via tyrosine hydroxylase
Dopamine is a precursor to what molecules
norepinephrine and epinephrine
how is epinephrine formed
tyrosine > DOPA > dopamine > norepinephrine > epinephrine
rate limiting step in catecholamine production
Hydroxylation of tyrosine by tyrosine hydroxylase
Metyrosine
binds tyrosine hydroxylase but cannot be transformed to DOPA, decreasing dopamine production. Used for hypertension bc it decreases the NE produced
L-DOPA
a precursor to dopamine. Used to treat Parkinson’s disease but increasing the amount of dopamine.
DOPA loading can have adverse effects of the CV system due to increased NE in the peripheral autonomic nerves
carbidopa
blocks the conversion of L-DOPA to dopamine.
does not cross the BBB. Can be used to decrease the cardiovascular side effects of L-DOPA in peripheral adrenergic nerves
B-hydroxylase what does it do and where is it located?
It transforms dopamine to norepinephrine. It is located within the vesicle so that the NE is not degraded by cytosolic enzymes
Vesicular monoamine transporter (VMAT)
is responsible for transporting dopamine into synaptic vesicles. Is specific to monamines (serotonin, NE, histamine, and dopamine)
reserpine
blocks VMAT resulting in depletion of monoamines (NE, DA, and serotonin).
can cross the BBB and block monoamine vesicular uptake in the CNA neurons contributing to depression
used at low doses to treat hypertension
Bretylium
inhibits excitability of the nerve terminal membrane and reduces neurotransmitter release.
affects adrenergic neurotransmission ( taken up by transporters that normally take up NE)
reduces ventricular arrhythmias
primary mode of terminating monoamine actions
reuptake
catecholamine-O-methyltransferase (COMT)
an enzyme in the plasma that inactivates NE by metabolism. The main termination of exogenously administered NE.
metabolizes circulating monomaines (exogenous and released by the adrenal gland)
Monamine Oxidase (MAO)
oxidizes norepinephrine and dopamine within the cytoplasm that is not transported into vesicles fast enough
cocaine
inhibits re-uptake of monoamines including NE, dopamine and serotonin
Common mechanism of drugs used to treat depression and anxiety
blocking/inhibiting monoamine reuptake
must be able to cross the BBB
can have significant systemic side effects (particularly CV which is richly innervated by noradrenergic neurons)
phenylephrine
drug that was developed to be resistant to COMT degradation and therefore has a longer half-life
activates adrenergic receptors
MAO inhibitors
lead to increased catecholamines in the cytoplasm.
As NE accumulates in the cytoplasm the transporter protein reverses direction leading to expulsion of NE into the synapse.
Tyramine
comes form a dietary source. normally has first pass metabolism by MAOs in the liver.
when MAOs are inhibited- tyramine accumulates and is transported into adrenergic cells where it competes with NE for transport into synaptic vesicles resulting in even higher level of cytoplasmic NE than with MAO inhibitors alone. Reversal of the reuptake transporter can then lead to a hypertensive crisis
neuropeptides
required longer increases in Ca to stimulate peptide release (bc they must travel further) and often produced within other neuronal types and are co-released when the nerve terminal is activated. therefore drugs that target membrane ion channels also affect neuropeptides (bertylium)
challenge for making peptigergic analogs
the are large and we don’t fully understand how they interact with their receptors and the cannot cross the BBB
therefore many non-peptidergic receptor agonist and antagonist have been developed for penetration into the CNS
naloxone
small lipophilic molecule used to reverse opioid overdose.
naltrexone
longer duration of action than naloxone and is used in the treatment of opiate addiction and alcoholism
ways neuropeptides differ from classical
neurotransmission
Requires mRNA for synthesis
Peptidases required to make final neurotransmitter*
Stored in “large dense core vesicles”
Made in soma and transported
Stored away from synapse, and requires longer stimulus for release
Travel farther to bind receptor*
Non-specific peptidase-induced metabolism
