Intro CNS II: Neurotransmitters Flashcards by Meghan May

Noradrenergic neurons (i.e. neurons that utilize norepinephrine) are located in the

medulla oblongata, pons and midbrain called the reticular activating system

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a prototype catecholamine

Norepinephrine

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Very important in arousal (wakefulness) and in regulation of autonomic functions like breathing and blood pressure

Nepi

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Nepi must be made in the brain bc

can’t cross the BBB

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Nepi is made from

tyrosine, taken across the BBB

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tyrosine is converted to 3,4-dihydroxyphenylalanine (DOPA) by

tyrosine hydroxylase

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DOPA is converted into dopamine by

DOPA decarboxylase

a) low substrate specificity

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dopamine is converted into norepinephrine by

dopamine beta hydroxylase

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Primary regulation of norepinephrine synthesis occurs via

tyrosine hydroxylase (TH)

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TH is normally saturated with tyrosine so its activity is the rate limiting step for____ synthesis under basal conditions

DOPA

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TH has an essential co-factor

tetrahydrobiopterine, BH4

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Short-term regulation of tyrosine hydroxylase activity occurs via:

(1) phosphorylation at four different serine residues

(2) end-product (i.e. norepinephrine) inhibition of BH4 binding to the enzyme; this detects over-filled vesicles

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Synthesis of Nepi is tightly regulated; seems designed to maintain a constant amount that is released:

in a single synpatic vesicle

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Dopamine beta hydroxylase is located in______ and co released with_________

synaptic vessicles
with NE
(not well regulated)

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DOPA decarboxylase has _____substrate specificity and is found in

LOW

serotonergic neruons like astrocytes

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Tyrosine Hydroxylase is saturated with ______ at normal conc but not saturated with _____-

saturated with tyrosine

not saturated with tetrahydrobiopterine (BH4) co-factor

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Activity of tyrosine hydroxylase is regulated by

binding of BH4

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Where does the last step of synthesis of NE occur

Dopamine is taken into the vesicle, the last step of synthesis occurs there

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Vesicular monoamine transporters are called VMAT; VMAT2 is found

in the brain

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NE competes directly for BH4; the NE regulating BH4 binding is :

a specific regulatory pool present in cytosol

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Neuronal activity increases _____, which then actiates CaM kinase which increases affinity for BH4

Calcium

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What activates CaM kinsase

increase in neuronal activity–> increase in Ca++

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What results in decreased affinity of TH for BH4

inhibition of cAMP generation and decreased PKA activity

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Three mechanisms of norepinephrine release

a) calcium-dependent exocytosis of vesicles
b) reversal of plasma membrane transporters
c) dendritic release that is not calcium-dependent

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Release of NE is regulated by presynaptic receptors (autoreceptors) a) _______inhibits release b) _______ increases releas

alpha2 receptor | beta receptor

alpha 2 presynaptic receptor will _____ NE release

inhibit | called feed back regulation

Beta receptor on the presynaptic terminal will _____ NE release

increase | called feed forward regulation

All transmitters can be inactivated by

diffusion

_____ by the presynaptic neuron is the most important: neuronal not astrocytic

Reuptake

During reuptake: | High affinity carrier proteins move norepinephrine from _____ to ______ compartments

from extracellular to intracellular compartments

During reuptake of NE, this is a E requiring process via

Na+ co transporter

Reuptake for NE has a binding site for norepinephrine that is the site of action of _____

inhibitors

Once norepinephrine is intracellular, it can be

re-packaged into vesicles for release or degraded by enzymes

deaminates norepinephrine

Monoamine oxidase (MAO)

which form of MAO is found in the brain

MAOB

MEch of Catechol-O-methyl-transferase (COMT)

transfers a methyl group from S-adenosylmethionine to the meta OH of norepinephrine

Catechol-O-methyl-transferase (COMT)

Two enZ inactivations of NE

MAO | COMT

All 9 of the receptors for norepinephrine are

'adrenergic' G protein coupled

how are NE receptors classified

using structure activity releationships

Coupled to 2nd messenger that increases Ca++ and is found on non-neuronal cells in periphery

alpha 1

alpha 1 receptors are coupled to ______ and will _____ Ca++ found in non-neuronal cells

2nd messengers | increase

these inhibit adenyl cyclase and often present on presynaptic neourons; release-inhibiting autoreceptor

alpha 2

alpha 2 receptors _____ adenyl cyclase, are on presynaptic side and are

inhbit | release inhibiting autoreceptors

Beta receptors for NE will

increase adenly cyclase activity

Beta receptors all work to increase adenyl cyclase, the dif in Beta subtypes is

the tissue they are located in

What does adenyl cyclase do

generates cAMP and then activates PKA

Via alpha receptors we see that NE will

induce arousal/stimuation and information gating or focus like a traffic controller

Via beta receptors we see reguation of

sympathetic and PNS outflow such as BP control

Neurotensin is what kind of NT

neuropeptide

Neurotensis is ____ aa long and found in

13 aa long | prefrontal cortex and the hypothalamus in the midbrain

Neurotensin is always co-localized with

DA---- these two transmitters are utilized by same neurons

Seems that the peptides in general are _______ with other neurotransmitters and affect and are affected by these NTs.

co-localized

It's hypothesized that the neuropeptides add _______ to the simple signaling that could occur with a single transmitter

complexity, (“color”)

Co-transmission is a ___ and a ____

peptide and amine

Transmitting signals are different, not

redundant

Neurotensin starts as a _____ aa and then hydrophobic signal sequence will direct the protein to

170 | to the ER

At the Gogli, neurotensin is:

packed into secretory vesicles that containe peptidases where it's processed to one molecule of neurotensin and one neurmedin N

What results from going 170 precursorr of neurtoensin

processed in the golgi by peptidases to one Neurotensin and one neuromedin N

Neurotensin is stored in different type of vesicles that are NOT synaptic vesicles but are

secreatory vesicles: dense core

dense core secreatory vesicles for Neurotensin are smaller or larger then synpatic vesicles

larger

Neurotensin secreatory vesicles are transported to axons via

secratory path

Neurotensin secreatory vesicles concentration as terminals

low, variable

Release of Neurotensin is ________, but require high intensity, rapid firing of neurons to be released

calcium dependent

What is special about neurotensin release

Release is not necessarily at the active zone; can be released anywhere along the membrane and is not recaptured

Regulation of inactivation of neurotensin

1. Nonselective peptidases cleave the peptide 2. Diffusion 3. No reuptake by transporters a) However, peptide bound to receptor can be internalized along with the receptor and is transported up to the cell body and may be functional there

peptides tend to _______that is, they are more persistent at their receptors than the amine neurotransmitters

“last longer”;

Compared to the inactivation of glutamate, inactivation of neorotensin is:

more haphazard, | singnaling is LESS directed and can last longer with lower fidelity

Receptors for Neurotensin

GCRP with many bonds bc neurtensin is so large and will have higher affinity binding

The higher affinity binding and more bonds forming btw neurotensin and R may compensate for:

lower amounts released and distance needed to travel