Nt's & Hormones

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NT's

Back 1

-Ca dependent release
-made by neurons
-stored in synaptic vesicles
-rapid inactivation

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Types

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-AcH
-biogenic amines
-peptides
-amino acids

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AcH

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Acetyl CoA + choline --[choline-acetyl transferase]>> acetylcholine
-Acetylcholine reacts with the OH group of serine on the enzyme to breakdown into acetyl CoA and choline
- at the neuromuscular junction
-myelinated axon conduct stimulus
-sodium flux across the membrane for depolarization
-when open, positive charges are carried in
-when the membrane depolarizes, channels open from the axon to the terminal
voltage gated calcium channels
-channels normally closed
-opened when depolarized
-Ca binds to proteins inside, packed with Ach
-Ach pumped into synaptic vesicles, fuses with membrane, and is released out
-Ach binds to receptors on the muscle fiber, and opens allowing Na to rush in and depolarize the muscle cell

Front 4

Biogenic amines

Back 4

-from aromatic amino acids
-made by cells of neuroectodermal origin
-neurotransmitters, hormones, and local messengers
-water-soluble
-stored in vesicles
-released by exocytosis
-rapid inactivation

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Types of biogenic amines

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-tyrosine ->catecholamines (dopamine, norepinephrine, epinephrine)
-tryptophan ->serotonin (5-HT)
-histidine ->histamine

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Catecholamine formation

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cytoplasm
L-tyrosine --[tyrosine hydroxylase]>> L-DOPA(commited step) --[DOPA decarboxylase]
>>Dopamine
storage granules
--[dopamine Beta-hydroxylase]>> norepinephrine -[phenylethanolamine N-methyltransferase]>> epinephrine

-tyrosine hydroxylase adds OH group to the benzene ring of L-tyrosine to make L-DOPA (the commited step)
DOPA decarboxylase removes the carboxyl from DOPA as CO2 to make dopamine
dopamine Beta-hydroxylase to make norepinephrine
phenylethanolamine N-transferase adds the methyl to the amine to make epinephrine

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Catecholamine inactivation

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imp for intracellular enzymatic deactivation and inactivation of their biological fnxs
1.uptake into cell
2.MAO monoamine oxidase (deamination) – instead of amino group, it adds an o2
-an oxidative type reaction, reduces FAD to FADH2
-H2 from FADH2 combines with oxygen to make hydrogen peroxide (potentially toxic)
-primary amino groups of dopamine and norepinephrine, secondary amino group of epinephrine are removed
3.COMT catechol O-methyltransferase (methylation)
-Hydroxy group in the ring gets a methyl
4.MAO, COMT, Aldehyde dehydrogenase
-Dopamine->homovanillic acid (MAO-B)
-Norepinephrine -> Vanillylmandelic acid (MAO-A)
-Epinephrine -> Vanillylmandelic acid

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Synthesis and degredation of serotonin

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L-tryptophan --[tryptophan hydroxylase]>> 5 hydroxytryptophan --[decarboxylase]>> 5-HT (serotonin)
-Inactivation of serotonin is by MAO only
- MAO-A acts on serotonin (and norepinephrine)
-Enzymes actions similar to tyrosine
-biogenic amines are not degraded in the synaptic cleft
-their synaptic action is terminated by sodium dependent, high affinity uptake back into the nerve terminal

Front 9

Peptide NT's

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-formed from precursor proteins
-synthesized in perikaryon
-inactivated by peptidases
-EXAMPLES: endorphins, TRH, cholecystokinin, substance P…

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Amino acid NT's

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-no biosynthetic and inactivating enzymes
-accumulation in synaptic vesicles
-high-affinity uptake from synaptic cleft
-EXAMPLES:
glutamate, aspartate (excitatory)
glycine (inhibitory)
Glutamate --[glutamate decarboxylase (B6)]>> GABA --[GABA transaminase (B6)]>> succinic semialdehyde
-alpha-carboxy group is removed by glutamate decarboxylase

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NT actions

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NT's change the membrane potential of the postsynaptic cell by opening (or closing) ion channels:
-Excitatory neurotransmitters
-Inhibitory neurotransmitters

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Ligand gated ion channels

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-ion channels closed in the resting state but open with the NT binds
Examples:
-nicotinic acetylcholine receptor: A sodium channel present in NMJ autonomic ganglia, and brain
-NMDA glutamate receptor: present in the brain important for synaptic modification in the limbic system
-GABA-A receptor: a chlorine channel in the brain mediates the effects of barbiturates and benzodiazepines
-Glycine receptors: A chloride channel in brain stem and spinal cord blocked by strychnine

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G-linked protein receptors

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common variety of hormone receptor, but also used by NT's linked to 2nd messengers
-adrenergic receptors: linked to cAMP (beta receptors, alpha 2-receptors) or IP3 (alpha 1-receptors)
-dopamine receptors: either stimulation of cAMP (D1 receptors) or inhibition of cAMP (D2 receptors)
-muscarinic acetyhlcholine receptors: different subtypes linked to IP3 and or inhibition of cAMP
-opiate receptors: designed for endogenous opioid peptides, inhibitory coupling to cAMP