Lecture 36: Neuropharm, Catecholamines and Sympathetic NS Flashcards
What is neurotransmitter of parasympathetic system?
ACh
What is only sympathetic innervation that has Ach as postganglionic neurotransmitter?
Sweat glands
What is sympathetic nervous systems association with psychiatry?
SNS regulates mood and attention
What are the primary neurotransmitters of sympathetic nervous system?
- NE
- epinephrine
- Dopamine
- Serotonin
Can be unique and all together
What are the cotransmitters that are used to modulate the primary neurotransmitters of sympathetic system?
- ATP
- Galanin
- Neuropeptide Y
What is the significance of neuropeptide Y?
A cotransmitter of sympathetic NS
What is the significance of Galanin?
A cotransmitter (neuropeptide) of sympathetic NS
What is the significance of ATP for neurotransmission?
A cotransmitter of sympathetic NS
What is the rate-limiting step in the biosynthesis of catecholamines? How is it regulated?
Rate limiting step = tyrosine to dopa by tyrosine hydroxylase
Regulation by phosphorylation (PKA and PKC signaling pathway): acute mechanism for increasing synthesis
-delayed increase in tyrosine hydroxylase gene expression after nerve stimulation
Why is it important to memorize synthesis of catecholamines?
Targets for therapy
What neurotransmitter is Tryptophan a precursor for?
Serotonin
What neurotransmitter is TYROSINE a precursor for?
Dopamine, NE and epinephrine
What is the difference between serotonin and dopamine, ne and epinephrine synthesis?
Serotonin starts with tryptophan
The others start with TYROSINE
What is the order of synthesis of catecholamines?
- Tyrosine
- DOPA
- Dopamine
- Norepinephrine
- Epinephrine
What is the enzyme that converts tyrosine to DOPA? Significance?
Tyrosine hydroxylase
Rate-limiting step
Tryptophan hydroxylase is the rate limiting step for
Serotonin synthesis
Tyrosine hydroxylase is rate limiting step for
Dopamine synthesis
What is the enzyme that that converts Dopa to Dopamine?
i-Aromatic amino acid DECARBOXYLASE
What is the enzyme that converts dopamine to NE?
DOPAMINE Beta-hydroxylase
What is the enzyme that converts NE to epinephrine?
Phenylethanolamine N-methyltransferase (PNMT)
Mnemonic: Phenylethanolamine is another name for NE lol
Phenylethanolamine N-methyltransferase (PNMT)
Mnemonic: Phenylethanolamine is another name for NE lol
Enzyme that converts dopa to dopamine
What is phenylethanolamine N-methyltransferase?
Enzyme that converts NE to E
What leads to increase of catecholamine synthesis?
Stress!
Fight or Flight
What is contained in catecholaminergic vesicles?
catecholamines, ATP, dopamine beta hydroxylase, ascorbic acid and NPY
What is negative feedback loop of catecholamines?
Large amount of dopamine and NE can inhibit tyrosine hydroxylase
What are the two cell types of adrenal medulla?
- those with norepinephrine only (no phenylethanolamine-N-methyltransferase…PNMT)
- those with primarily epinephrine (DOES contain PNMT)
How is PNMT regulated?
It is regulated by glucocorticoids (cortisol) secreted by adrenal cortex
What does the adrenal cortex secrete?
Glucocorticoids (cortisol)
What does the adrenal medulla secrete?
Catecholamines
NE and epinephrine
How are catecholamines stored?
In nerve endings, catecholamines are stored in vesicles where they are protected from degradation
-in adrenal medulla, they are stored in granules
Is the vesicle reuptake energy dependent or not? Significance?
It IS ATP dependent
Significant because ATP can be taken up and can be ratelimiting
How do you release catecholamines?
-membranes also allow slow leakage of amines out of vesicles
-but this is inconsequential
Exocytotic release of vesicle contents is CALCIUM dependent
How does calcium regulate release vesicles?
Membrane bound Ca channel regulates intracellular Ca
Ca interacts with vesicle associated membrane proteins (VAMP) and triggers fusion of the vesicular membrane with the terminal membrane and release of norepinephrine
What is the significance of vesicle associated membrane proteins (VAMP)?
VAMP interacts with Ca to mediate vesicle release
What are autoreceptors (heteroreceptors)?
Sit on presynaptic terminal
A receptor on the PREsynaptic terminal that binds to the neurotransmitters
-binding of neurotransmitter…depending on the autorecptor…brings about different responses in terminal bouton
What happens when neuroepinephrine binds to alpha2-adrenergic autoreceptor? Beta-adrenergic autoreceptor?
Negative feedback of vesicle formation
Positive feedback for vesicle formation
What is important in GCPR?
The g-protein subunit determines the effect (Gq, Gi, Gs)
What are the different types of adrenoreceptors?
Alpha-1 = Gq = increase Ca Alpha -2 = Gi = decrease cyclic AMP Betas are (Gs) so increase cAMP
What do all receptor types except for
Beta-2 (Gs) bind to?
Both NE and E
Beta-2 only binds to Epi
What are the major factors determining actions of sympathomimetic amines?
- Relative potency of amine
- Proportion and density of various receptors
- whether or not you have more or less alpha vs. beta receptors…predicates the response in any given tissue
- Reflex or homeostatic adjustments made in response to actions produced by amine
e. g. acting like a man instead of squealing when you see a mouse - refractoriness/desensitization of the receptor
e. g.Beta-arrestin will internalize receptors and terminate ligand-receptor affinity
What is refractoriness?
Refers to once b-arrestin is there, you can’t bind the ligand
What gets transported via VMAT into vesicle?
Dopa gets converted to dopamine and is transported by VMAT into a vesicle
