Term
| synthesis of small molecule neurotransmitters |
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Definition
1. NT synthesis is regulated by neuronal activity levels
2. synthesis occurs in the cytosol
3. NTs are packaged in vesicles
4. cofactors include folic acid, SAM, O2, Cu, vitamins C, B6, B12 |
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Term
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Definition
1. assembled in terminal through endocytosis
2. NTs enter vesicles using transporter proteins in vesicular membrane
3. depends on vesicular ATPase that exchanges H+ for NTs
4. reserpine blocks transporter |
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Term
| neurotransmitter destinations |
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Definition
1. presynaptic receptors
2. postsynaptic receptors
3. diffusion out of synaptic cleft
4. enzymatic degradiation
5. reuptake across plasma membrane |
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Term
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Definition
1. pore in membrane for passage of ions
2. diversity is from variety of forms each subunit may have
3. age-dependent properties (can change) |
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Term
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Definition
1. coupled to G protein activation and second messenger pathways
2. diversity from different types of G proteins |
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Term
| Plasma membrane (pm) transporters |
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Definition
1. depend on transport of sodium and other ions to move transmitters into terminal against concentration gradient
2. can have several subtypes that vary in location and specificity but most drugs cannot take advantage of this and affect whole class |
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Term
| functions of plasma membrane reuptake |
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Definition
1. terminate action at receptor
2. prevent diffusion to other synapses
3. recycle supply
4. can run in reverse if NT levels are high intracellularly |
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Term
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Definition
| mimic neurotransmitters and bind to pm transporters then enter vesicles, displacing real NTs. The NTs accumulate in the cytosol resulting in a large leak through pm transporters out of terminal and massive stimulation of receptors. They may also be released from the vesicles at terminals and act as agonists or antagonists. |
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Term
| criteria for neurotransmitters |
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Definition
1. synthesized in neuron
2. stored in nerve terminal
3. released in quantities sufficient to affect postsynaptic cell
4. exogenous application mimics action
5. mechanism for removal |
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Term
| overview of steps in synaptic transmission |
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Definition
1. neurotransmitter synthesis
2. storage in vesicles
3. Ca entry
4. neurotransmitter release
5. binding to receptors
6. degradation in cleft, metabolism, or diffusion from synapse
7. reuptake
8. recycling of vesicles
9. neuromodulation by presynaptic receptors |
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Term
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Definition
the major excitatory NT in the CNS!
1. 70% synthesized by glutamine by glutaminase
2. glucose->->a-ketoglutarate-->glutamate (TCA cycle) |
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Term
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Definition
1. ionotropic (AMPA, NMDA, Kainate) and metabotropic receptors
2. primary mechanism for inactivation is reuptake by pm Glu transporter
3. astrocytes play a big role in inactivation and recycling - convert Glu to Gln via glutamine synthesis and transport it out of cell where neurons take it up via a glutamine transporter and convert it to Glu |
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Term
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Definition
elevated levels of Glu are neurotoxic and is released in excessive amounts by neurons in pathological conditions
it can activate many synapses and cause huge Ca++ release which kills neurons |
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Term
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Definition
1. pm Glu transporter is primarily on astrocytes
2. 5 subtypes differing in affinity, specificity, and location
3. highly effective at lowering extracellular Glu concentration - acts as buffer |
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Term
| GABA (gamma amino butyric acid) synthesis |
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Definition
glutamate->GABA by glutamic acid decarboxylase
the major inhibitory NT in CNS! - major importance in preventing overactivity in CNS |
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Term
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Definition
1. ionotropic: many modulatory sites where agonist and antagonist moleculres bind, agonists have synergistic effect
2. alcohol is a GABA agonist, also sites for benzodiazepines, bicuculline, barbiturates, steroids, and picrotoxin
3. metabotropic receptors |
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Term
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Definition
| through neurons and glia - 4 different pmGABA transporters |
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Term
| general characteristics of catecholamines |
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Definition
1. synthesized by small percentage of neurons but wide distribution of terminals in brain
2. excitatory, inhibitory, modulatory
3. all synthesized by tyrosine or indirectly from phenylalanine via PAH
4. one type of vesicular transporter in brain for all; another type in adrenal medulla. both inhibited by reserpine
5. all receptors are metabotropic
6. major mechanism for stopping action is reuptake - pm dopamine and pm NE/E transporters
7. degraded by 2 enzymes: MAO and COMT |
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Term
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Definition
tyrosin->Dopa (tyrosine hydroxylase)->dopamine (AADC)
tyrosine hydroxylase is rate-limiting and its activity is saturated at normal levels so adding more tyrosine wont contribute to more catecholamine synthesis (transporter for Phe and Tyr across BBB also saturated) |
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Term
| L-aromatic amino acid decarboxylase |
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Definition
AADC has broad specificity for amino acid substrates
carbidopa doesnt cross BBB and inhibits peripheral AADC to prevent conversion of dopa to dopamine which would affect gut and cause N/V |
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Term
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Definition
1.pmDopamine transporter (DAT)
2. inhibited by cocaine
3. amphetamines and neurotoxin MPP (kills dopaminergic neurons) are substrate for receptor |
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Term
| synthesis of norepinephrine |
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Definition
| synthesized in vesicle from dopamine by dopamine-B-hydroxylase, which is bound to the inner surface of the vesicle |
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Term
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Definition
pmNE transporter (NET)
inhibited by antidepressants and cocaine |
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Term
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Definition
| phenylalanine-N-methyltransferase (cytoplasmic) converts NE to E - NE needs to exit vesicle, convert, come back |
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Term
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Definition
present in neurons- localized to outer mitochondrial membrane
degrades monoamines not inside vesicles by deamination to aldehyde - regulates NT level
1. decrease availability of dietary monoamines (false transmitters) in gut
2. prevents dietary monoamines from crossing BBB |
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Term
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Definition
1. CNS and gut
2. substrate specificity: serotonin>NE>dopamine
3. breakdown dietary monoamines (tyramine), which gain entry into sympathetic neurons via pmMonoamine trasporter - displaces NE
4. irreversibly inhibited by clorgyline |
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Term
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Definition
1. CNS
2. substrate - prefers B-phenylethylamine
3. irreversibly inhibited by selegiline |
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Term
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Definition
| nonspecific irreversible inhibitors - increase presynaptic concentration of NTs and prolongs availability of released NTs |
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Term
| dangerous interactions with MAO inhibitors |
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Definition
when combined with foods containing tyramine, may result in release of large amounts of NE, inducing hypertensive crisis (tyramine displaces NE)
when combined with SSRIs or tricyclic antidepressants, which inhibit pm Serotonin transporter, Serotonergic Syndrome can occur - mental status change, myoclonus, hyperreflexia, fever, cardiovascular change |
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Term
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Definition
present in nervous system and peripheral tissues; extracellulary in synaptic cleft, degrades NT after release
broad catechol substrate specificity
methylates one of the hydroxyl groups
inhibitors: entacapone, tolcapone |
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Term
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Definition
synthesized from tryptophan, and essential AA that crosses BBB
tryptophan hydroxylase is rate-limiting enzyme |
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Term
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Definition
synaptic action stopped primarily by reuptake via specific pmSerotonin transporter (SERT)
inhibitors: SSRIs, tricyclic, cocaine
serotonin is metabolized by MAO |
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Term
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Definition
| from histidine (essentiall AA) via AADC |
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Term
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Definition
| MAO and histamine methyltransferase |
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Term
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Definition
Acetyl-CoA + choline->CoA + Acetylcholine-> choline +acetate
one step with choline acetyltransferase
choline is derived from diet and crosses BBB - synthesis limited by availability of choline |
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Term
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Definition
1. ionotropic receptors desensitize rapidly
2. enzymatic degradation by acetylcholine esterase in synaptic cleft - resulting choline taken up by pmCholine transporter
3. no reuptake transporter for ACh |
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Term
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Definition
1. dopamine: midbrain
2. NE: pons (locus ceruleus)
3. E: adrenal medulla
4. serotonin: midline nuclei of pons and medulla
5. histamine: hypothalamus
6. ACh: nuclei in pons and lower frontal lobe, cranial nerves and spinal motoneurons, sympathetic and parasympathetics |
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