Bioc L10 Neurotransmitters Flashcards
What are the two classes of neurotransmitters?
What do tyrosine, tryptophan and choline become?
Small nitrogen-containing molecules and neuropeptides. Small molecule transmitters are not polypeptides encoded by genes, they’re derived from precursor molecules, usually an amino acid.
- *Tyrosine** becomes dopamine, epinephrine or norepinephrine.
- *Tryptophan** becomes serotonin
- *Choline** becomes acetylcholine.
What are the catecholamines?
Epinephrine, norepinephrine, dopamine, and DOPA.
All derived from tyrosine.
What 2 cell types release epinephrine and norepinephrine and for what purpose?
Chromaffin cells of the adrenal medulla, innervated by splanchnic nerve of sympathetic nervous system, releases epi (80%) and norepi (20%) in response to stress (acetylcholine signal from sympathetic nerve termini).
The onle soure of circulating epinephrine and norepinephrine in the body.
Nerve termini release epi and norepi into synaptic cleft to signal postganglionic nerve neurons. Norepi is the principal neurotransmitter for sympathetic nerve termini. Epi is only released by a few types of nerve termini.
How do epinephrine and norepinephrine differ in effect on peripheral tissue?
80% is epinephrine which has a more potent effect on peripheral tissue (physiological response seen at much lower concentrations than for norepinephrine).
What is the paradigm of synaptic signaling (norepi example)?
NE = Norepinephrine
NET = Norepinephrine transporter (for norepi
reuptake)
VMAT = vesicular monoamine transporter, an antiporter that exports a proton for every catecholamine it imports into the vesicle (secondary active transport). A vesicular ATPase is utilized to generate a proton gradient on the inside of the vesicle to maintain a low pH.
What type signaling occurs in synaptic signaling vs signaling from the adrenal medulla.
Both release epi/norepi that bind to adrenergic receptors (GPCRs, α1, α2, β) on effector cells.
Synaptic signaling = autocrine/paracrine
Adrrena medulla signaling = endocrine
How and where is norepinephrine synthesized in neurons?
In the cytoplasm:
Tyrosine is converted to DOPA by tyrosin hydroxylase
DOPA is converted to Dopamine by L-Aromatic Amino Acid Decarboxylase
In Vesicle:
Dopamine is converted to norepinephrine by dopamine B-Hydroxylase
Then, norepinephrine either binds to receptors, gets degraded, or is transported back into cytoplasm
What is the chemical structure of Catechol?
What is the structure of Tyrosine, DOPA, Dopamine, Norepinephrine and Epinephrine?
Think of the 4 steps: hydroxylation, decarboxylation, hydroxylation then metheylation and start from Tyrosine (image below)
Catechol is a benzene ring with two -OH groups
DOPA is the first catecholamine, hydroxylation adds OH to benzene ring.
Dopamine results from the decarboxylation of DOPA
Norepi results from hydroxylation of the first Carbon in the chain.
Epi results from methylation of terminal nitrogen on the chain.
Step 1 of catecholamine synthesis:
Tyrosine hydroxylase (TH) catalyzes the first and rate-limiting step in catecholamine synthesis.
TH requires a cofactor called tetrahydrobiopterin (BH4),
which donates electrons to the reaction.
TH catalzyes the hydroxylation of tyrosine to form
L-dihydroxyphenylalanine (L-DOPA), the first catecholamine in the pathway.
Clinical Correlate: Tetrahydrobiopterin (BH4) Deficiency: What does it affect?
What is the treatment?
Tetrahydrobiopterin (BH4) functions as a cofactor for three enzymes important to neurotransmitter synthesis:
• phenylalanine hydroxylase (which produces tyrosine in the liver)
• tyrosine hydroxylase (used in catecholamine synthesis)
• tryptophan hydroxylase (used in serotonin synthesis)
Individuals with genetic deficiencies of BH4 exhibit neurological deterioration that is unresolved by reducing phenylalanine intake (clinically termed
“malignant PKU”).
FDA approved sapropterin, a synthetic analog of BH4 that is now being used to treat BH4 deficiencies and certain types of PKU.
Step 2 of catecholamine synthesis.
L-dopa is decarboxylated by the enzyme Amino Acid Decarboxylase (in this step, also referred to as DOPA decarboxylase) to form Dopamine
Vitamin B6 (pyridoxal phosphate) is a necessary cofactor for this reaction.
In dopaminergic neurons (those that release
dopamine into the synaptic cleft), metabolism of catecholamines ceases at this point because dopaminergic neurons do not synthesize the necessary enzymes (β-hydroxylase; PNMT) to continue metabolism of dopamine.
Step 3 of catecholamine synthesis:
Hydroxylation of dopamine to produce Norepinephrine
In cells that make epinephrine or norepinephrine, dopamine is imported into storage vesicles.
Dopamine is then hydroxylated by the vesicle-resident enzyme dopamine β-hydroxylase.
The product of this reaction is norepinephrine.
Ascorbic acid (Vitamin C) acts as an electron donor for this reaction.
Copper (Cu2+) is a bound cofactor that
is required for electron transfer.
In the majority of neurons which synthesize norepinephrine, and a portion of adrenal medulla chromaffin cells, catecholamine synthesis ends at
this step.
Step 4 of catecholamine synthesis:
Methylation of norepinephrine produces epinephrine
Approximately 80% of the chromaffin cells of the adrenal medulla express the enzyme phenylethanolamine N-methytransferase (PNMT)
PNMT catalyzes the methylation of norepinephrine, forming epinephrine. (PNMT catalyzes methylation of norepinephrine that has leaked from storage vesicles.)
S-adenosyl methionine (SAMe) donates a methyl group for this reaction.
The 20% of chromaffin cells that do
not express PNMT release norepinephrine upon stimulation, rather than epinephrine.
A small subset of neurons also express PNMT and are able to secrete epinephrine for localized synaptic signaling.
How is PNMT regulated?
Cortisol is main regulator of PNMT synthesis (and tyrosine hydroxylase and dopamine β-hydroxylase)
Cortisol released by adrenal cortex flows to the medulla and prepares body for “anticipated stress”, increasing epinephrine stores that can be released when needed.
Catecholine signaling: Where do the different neurotransmitters function?
What are some effects of catecholamine neurotransmitters?
Norepinephrine and epinephrine bind to adrenergic GPCRs on postsynaptic cell or target tissue.
Dopamine binds to dopaminergic GPCRs
Catelcholamine receptors can induce vasoconstriction, gastric motility, bronchodilation, muscle contraction.
These receptors are also critical for the metabolic effects of circulating epinephrine on peripheral tissue metabolism (lipolysis, insulin and glucagon release, gluconeogenesis)
What are the characteristics of the GPCRs?
- *α1** adrenergic receptor: Gα-q Coupled GPCR
- *increases**: Protein kinase C Activity, Cytoplasmic Ca2+ , Calmodulin-dependent activities, CaM Kinase II
- *α2**-adrenergic receptor: Gα-i Coupled GPCR
- *decreases:** cAMP synthesis, protein kinase A activity
- *β**-adrenergic receptors: Gα-s Coupled GPCR
- *Increases:** cAMP activity, PKA activity
Describe the 3 ways tyrosine hydroxylase is regulated
- Feedback inhibition: binding of a catecholamine displaces BH4 cofactor, reducing TH activity
- Depolarization: increases kinase activities of PKC, PKA and CaM kinases. Phosphorylation of TH strengthens TH’s affinity for BH4, makes TH resistant to feedback inhibition.
- Phosphorylation of CREB Transcription Factor: binds to TH promoter and increases TH expression.
What is Pheochromocytoma and how can it be identified?
Pheochromocytomas are tumors of the chromaffin cells of the adrenal gland, and are characterized by a gross overproduction of epinephrine and norepinephrine.
High blood pressure is the main symptom of pheochromocytoma.
This condition can be identified through abnormal increases in catecholamine breakdown products present in 24-hour urine samples: normatanephrine,
metanephrine, and vanillylmandelic acid.
These molecules are part of the degradation pathway of circulating catecholamines in the liver.
How is the issue of dopamine not being able to cross the blood brain barrier being addressed in Parkinson Disease?
The dopamine precursor L-Dopa can cross the blood brain barrier but is subject to degradation by extracerebral dopamine decarboxylase (aka amino acid decarboxylase) or COMT before it reaches the barrier.
L-Dopa, sold as levadopa is combined with DDC inhibitor and COMT inhibitor to increase the amount of L-Dopa that makes it to the brain to be converted to Dopamine.
How is Serotonin Synthesized?
Why are SSRIs used to treat depression?
The synthesis of serotonin is very similar to that of norepinephrine from tyrosine.
Tryptophan serves as the initial substrate for synthesis, and is hydroxylated in by the BH4-dependent (and rate limiting) enzyme tryptophan hydroxylase.
The product, 5-hydroxytryptophan, is decarboxylated by amino acid decarboxylase to yield 5-hydroxy tryptamine (5-HT), also called serotonin.
SSRIs increase synaptic levels of serotonin which is thought to relieve depression.
