Glutamatergic physiology Flashcards

1
Q

nearly all CNS drugs produce their therapeutic effects by …….. ?

A

modifying certain steps in neurotransmission

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2
Q

what is the main excitatory neurotransmitter?

A

glutamate

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3
Q

how much glutamate synapses are there in the CNS?

A

50%

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4
Q

what are the steps/properties for glutamate metabolism?

A

synthesis
storage
release
deactivation

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5
Q

what is the precursor for glutamate?

A

alpha-ketoglutarate

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6
Q

what enzyme converts alpha-keto to glutamate?

A

GABA-transaminase aka GABA-T

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7
Q

what is H+-ATPase?

A

it is a primary active transporter that generate a proton gradient inside the vesicle

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8
Q

what is the proton gradient used for?

A

to transport glutamate inside the vesicle

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9
Q

what transporter transport glutamate into the vesicle?

A

VGLUT; an antiport
using the proton gradient to transport glutamate inside and proton outside simultaneously

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10
Q

what starts the process of glutamate release?

A

an action potential generated and reach the cell membrane

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11
Q

what happens after an action potential is generated?

A

an influx of Ca2+ into the nerve cell, increasing the cytosolic Ca2+, causing the movement of the vesicle towards the membrane

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12
Q

what are the two ways glutamate can be deactivated?

A

by re-uptake into the presynaptic nerve terminal by Gt(n) transporter

by uptake into glial cells by glial Gt(g) transporter

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13
Q

what does uptake into glial cell provide?

A

an additional source for glutamate release

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14
Q

what happens after glutamate is uptake into glial cells?

A

glutamate –> glutamine by enzyme glutamine synthetase

glutamine transferred to presynaptic terminal by glutamine transporters

glutamine —> glutamate by enzyme mitochondria-associated glutaminase

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15
Q

what are the two types of glutamate receptors?

A

ionotropic receptors
metabotropbic receptors

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16
Q

what are ionotropic receptors?

A

ligand-gated ion channels
permeable for Ca, Na, and K ions

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17
Q

what are metabotropic receptors?

A

GPCR receptors

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18
Q

what are the 3 ionotropic subtype receptors?

A

AMPA
kainate
NMDA

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19
Q

what kind of response are ionotropic?

A

fast and excitatorye

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20
Q

what kind of response is metabotropic?

A

slow response

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21
Q

what can block NMDA receptors?

A

Mg2+

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22
Q

how can NMDA block be removed?

A

needs a membrane depolarization to remove Mg2+ block

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23
Q

where are AMPA-r located?

A

thru out CNS, mainly hippocampus and cerebral cortex

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24
Q

what are the agonist for AMPA-r?

A

glutamate
AMPA

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25
Q

what is the major action of AMPA-r?

A

increase Na+ influx

26
Q

what is the minor action of AMPA-r?

A

increase K+ efflux

27
Q

where are kainate-r located?

A

thru out CNS, mainly hippocampus and cerebellum

28
Q

what are the agonists for kainate-r?

A

glutamate
kainate

29
Q

what is the major action of kainate?

A

increase Na+ influx

30
Q

what is the minor action of kainate?

A

increase K+ efflux

31
Q

where are NMDA-r located?

A

primarily hippocampus, cerebral cortex and spinal cord

32
Q

what are the agonists for NMDA-r?

A

glutamate
NMDA
glycine, membrane depolarization are needed along with NMDA for the receptor to be activated

33
Q

what is the major action of NMDA?

A

increase Ca2+ influx
increase K+ efflux

34
Q

what happens when there’s an influx of Ca or Na?

A

strongly depolarize the membrane, generating an action potential

35
Q

about 50% of drugs target which type of receptor?

A

GPCR

36
Q

what are the 3 types of GPCR-r?

A

G-alpha-s
G-alpha-i
G-alpha-q

37
Q

what is G-alpha-s?

A

excitatory

38
Q

what is G-alpha-i?

A

inhibitory

39
Q

what is G-alpha-q?

A

excitatory

40
Q

how does G-alpha-s works?

A

ACTIVATEs adenylyl cyclase (AC) —> increase cAMP —> increase PKA —> increase protein phosphorylation –> increase neuronal activity

41
Q

how does G-alpha-i works?

A

INHIBITS adenylyl cyclase –> decrease cAMP —> decrease PKA —> decrease protein phosphorylation —> decrease neuronal activity

42
Q

how does G-alpha-q works?

A

ACTIVATES phospholipase C (PLC) —> increase IP3 and DAG —> increase cytosolic Ca2+ from ER and PKC –> increase protein phosphorylation —> increase neuronal activity

43
Q

what is the most fundamental property of the nervous system?

A

neurotransmission

44
Q

how to know when a G protein is activated?

A

when the alpha subunit is bounded by GTP
inactivated when alpha subunit is bounded to GDP

45
Q

what does DAG do?

A

increase PKC - protein kinase C

46
Q

what happens during postsynaptic modulation?

A

when the post synaptic neurons are activated it can affect the AC and PLC pathway thru activated alpha subunit

thru beta-gamma subunits will affect K efflux and Ca influx

47
Q

what is presynaptic negative feedback modulation?

A

this is to reduce glutamate release when there’s already too much glutamate in the synaptic cleft
maintaining glutamate homeostasis

48
Q

what happens when presynaptic modulation is activated?

A

inhibition of Ca2+ channel which inhibits exocytosis of glutamate release

49
Q

what GPCR subtypes is in group 1?

A

mGluR1
mGluR5

50
Q

where is group 1 GPCR receptors located?

A

postsynaptic neurons

51
Q

what does group 1 GPCR receptors do?

A

activate AC and PLC pathways
increase neuronal activity
inhibits K channel, decrease K efflux which increase neuronal excitability

52
Q

what GPCR subtypes are in group 2?

A

mGluR2
mGluR3

53
Q

where do GPCR group 2 located?

A

post and presynaptic neurons

54
Q

what does group 2 GPCR receptors do in postsynaptic?

A

inhibits AC –> decrease cAMP –> decrease PKA –> decrease neuronal activity

activates K channels –> increase K efflux –> decreased neuronal excitability

55
Q

what does group 2 GPCR receptors do in presynaptic?

A

inhibits AC –> decrease cAMP –> decrease PKA –> decrease neuronal activity

inhibits Ca2+ channel –> decrease cAMP –> decrease Ca influx –> decrease glutamate release –> decrease neuronal excitability

56
Q

what GPCR subtypes are in group 3?

A

mGluR4
mGluR6
mGluR7
mGluR8

57
Q

where does group 3 GPCR located?

A

presynaptic

58
Q

what does group 3 GPCR receptors do in presynaptic?

A

inhibits AC –> decrease cAMP –> decrease PKA –> decrease neuronal activity

inhibits Ca2+ –> decrease Ca influx –> decrease glutamate release –> decrease neuronal excitability

59
Q

which type of GPCR receptor have direct effects?

A

ionotropic: NMDA, kainate, AMPA

THIS IS THE MAJOR MECHANISM OF GLUTAMATERGIC SYSTEM

60
Q

which type of GPCR receptor have indirect mixed effects?

A

GPCR

61
Q

what is the important mechanism of group 3 GPCR receptors?

A

to provide negative feedback mechanism when there’s too much glutamate