L8 - Amino Acid transporters Flashcards

1
Q

what determines whether an AP is fired?

A

whether the summation of EPSPs and IPSPs (temporal and spatial) reaches the threshold for an AP (-55mV)

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2
Q

what effect does glutamate have when acting on ionotropic receptors

A

excitatory (fast acting)

opening of Na+ / K+ channels (equally permeable)

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3
Q

what effect does glutamate acting on metabotropic receptors havve

A

slower acting inhibitory effect (increase IPSPs) (presynaptic inhibition and modifying frequency of postsynaptic APs)

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4
Q

what effect does GABA have when acting on
ionotropic
metabotropic
receptors

A

inhibitory effect on both

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5
Q

what effect does glycine have and what type of receptor does it act on?

A

inhibitory
ionotropic

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6
Q

where is glutamate synthesised? and why is this important

A

synthesised in brain from glucose metabolism
or from glutamine in astrocytes

important as glutamate cant cross BBB

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7
Q

what is the name of the vesicular glutamate transporters

A

VGluT 1-3

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8
Q

how is a concentration gradient maintained for the transport of NT into vesicles?

A

H+ ATPase actively pumps H+ into vesicles
each NT transporter can then use this [H+] gradient to transport NT into vesicles via antiport

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9
Q

how is Gutamine transported into glial cells?

A

EAAT (transporter)
using co transport of 2Na / 3H+ into glial cell
or counter-transport of K+

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10
Q

what are the three classes of ionotropic glutamate receptors

A

NMDA
AMPA
Kainate

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11
Q

what are the NMDA receptor channels permeable to

A

Na+
K+
Ca2+

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12
Q

what are the AMPA receptor channels permeable to

A

all permeable to Na+ / K+
some permeable to Ca2+

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13
Q

what are kainate receptor channels permeable to?

A

Na+
K+
Ca2+

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14
Q

where are kainate receptors mostly found

A

pre-synaptically - modulate NT release

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15
Q

how many subunits are there for the AMPA receptor (name them) and how do they exist in the receptor

A

4
GluA1-4

receptor is a tetramer

subunits exist in pairs, so the receptor will be 2x one type and 2x another type (eg 2x GluA1 and 2x GluA2)

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16
Q

how many subunits does the NMDA receptor have (name them) and how do they exist in the receptor (how many of each type)

A

5
GluN1
GluN2 (A-D)

receptor is a tetramer
subunits exist as 2x GluN1 then 2x any of the GluN2 subunits

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17
Q

how many subunits does the Kainate receptor have (name them) and how do they exist in the receptor (how many of each type)

A

5
GluK1-5

tetramer
GluK1-3 can form homomeric receptors, or can combine with 2x another subunit (always pairs)

GluK4-5 have to combine with 2x GluK1-3 (2+2) to be functional

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18
Q

where in brain are AMPA and NMDA receptors found

A

the different subunit types can be found in diifferent brain regions but AMPA and NMDA are generally found at the same functional excitatory synapses

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19
Q

why is GluN1 expressed in all brain regions?

A

because a fucntional NMDA receptor must have 2x GluN1 subunits

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20
Q

describe the speed of activation and inactivation of AMPA receptors

A
fast acting (fast depolarisation) 
fast decay (inactivation)
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21
Q

why is the AMPA receptor fastly inactivating?

A

due to relatively low affinity for Glutamate

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22
Q

describe the speed of activation and inactivation of NMDA receptors

A

slower activating
slower inactivating

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23
Q

why is the NMDA slower inactivating than the AMPA

A

NMDA has a higher affinity for glutamate - glutamate stays bound for longer so the channel may open and close several times before glutamate dissociates

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24
Q

why is the NMDA receptor slower activating?

A

its voltage sensitive

at membrane potentials more negative than -50mV, the channel opens but is blocked by a Mg2+ ion (trying to flow into the negative cell as its positive)
as the membrane becomes more depolarised (-40mV) the Mg2+ is less attracted and so the channel is unblocked

25
Q

what is the significance of the slower activating NMDA receptor

A

allows summation of non-synchronous inputs (not arriving at same time)

multiple inputs are required to relieve the Mg2+ block - so AMPA receptors can sense activity of many synaptic inputs on one cell

26
Q

what subunit of the NMDA receptor does glutamate bind

what other binding is required for this receptor to be activated?

A

GluN2

glycine binding to the GluN1 subunit

27
Q

describe the EPSPs of kainate receptors

A

relatively long lasting (similar to NMDA), only seen at few synapses

28
Q

what effect does Kainate receptor activation have?

A

presynaptically -> modulates NT release

post synaptically -> increase excitability of neurones via unknown G-Protein mechanim

29
Q

how many types of Glutamate metabotropic receptors are known

A

8
grouped into 3 subgroups

30
Q

what are the 3 subgroups of mGluRs and what G protein are they coupled to

A

Group 1 (mGluR1 &5) → (Gq)

Group 2 (mGluR 2&3) → Gi/Go

Group 3 (mGluR4,6,7,8) → Gi/Go

31
Q

describe the group 1 mGluRs (what types included, what G protein coupled to and what is their function

A

Group 1 (mGluR1 &5) (Gq) -> alpha subunit activates phospholipase C producing DAG and IP3,

  • IP3 triggers Ca2+ release (from ER/SR) increasing intracellular [Ca2+]
  • DAG activates PKC which can then phosphorylate proteins

By subunit modifies ion channel activity

32
Q

describe the group 2&3 mGluRs (what types included, what G protein coupled to and what is their function

A

Group 2 (mGluR 2&3) → Gi/Go

Group 3 (mGluR4,6,7,8) → Gi/Go

all have the same function →

  • a subunit inhibit adenylyl cyclase decreasing cAMP levels
  • by subunit mmodifies ion channel activity
33
Q

what are the mGluRs grouped according to?

A

AA sequence

agonist pharmacology

signal transduction pathways

34
Q

what effect does the By subunit of g protein linked mGluRs have pesynaptically

A

inhibit VGCC opening (less NT release)

interact with exocytosis mechanims to inhibit NT release

35
Q

what effect does the By subunit of g protein linked mGluRs have postsynaptically

A

modify K+ channel activity (opening them) causing hyperpolarisation

36
Q

where in the body is GABA found

A

brain

pancreas

no where else in body at significant concentrations

37
Q

describe GABA synthesis

A

glutamate → GABA via GAD(glutamic acid decarboxylase)

38
Q

describe degradation of GABA

A

GABA → succinic semialdehyde via GABA transaminase

39
Q

describe function of vigabratin

A

irreversibly inhibits GABA transaminase causing increased GABA levels

40
Q

name the vesicular GABA transporters

A

VIATT (also for glycine)

41
Q

describe reuptake of GABA

A
  1. into astrocyte via Na cotransport where its degraded
  2. uptake into presynaptic terminal where its reused
  3. uptake into postsynaptic neurones where its destroyed
42
Q

where are ionotropic GABA(A) receptors found

A

post synaptically

43
Q

describe the structure of the (ionotropic) GABA(a) receptor

A

5 subunits (2a, 2B, 1y)

each subunit has 4 TMDs

(nAChR like)

44
Q

where on the GABA(A) receptor (ionotropic) does GABA bind

A

between the a and B subunits

(2 binding sites as there are 2xB and 2xa

45
Q

which of the GABA receptors

GABAA

GABAB

is ionotropic and which is metabotropic

A

GABAA ionotropic

GABAB metabotropic

46
Q

where are (metabotropic) GABA(B) receptors found

A

pre and post synaptically

47
Q

what is the difference between GABA(A) and (B) inhibition?

A

GABA(B) is slower onset but longer lasting inhibition

48
Q

what effect can GABA(A) antagonists have?

A

convulsions (epilepsy)

49
Q

describe structure of GABA(B) receptor

A

GPCR

fucntional receptor acts as a dimer

7TMDs

50
Q

describe the dimer of the GABA(B) receptor

A

dimer exists between GABA(B)1 and GABA(B)2

GABA binds to GABA(B)1 and the G protein is associated with GABA(B)2 side of dimer

51
Q

what G protein is GABA(B) coupled to and what effect does this have

A

Gi/o

  • a subunit inhibits adenylate cyclase
  • By subunits act on channels (presynaptically inhibits Ca2+ channel opnening) (post synaptically opening K channels causing hyperpolarisation)
52
Q

where is glycine especially active and what is its function

A

spinal cord and brainstem → regulation of motorneurone activity

also found in retina and auditory systems

inhibitory

53
Q

describe glycine synthesis

A

L-serine → glycine via serine hydroxymethyl transferase

54
Q

what enzyme converts L-serine to glycine

A

serine hydroxymethyl transferase

55
Q

describe reuptake of glycine

A

into astrocyted via Na gradient

into pre and post synaptic membranes

56
Q

what type of receptor is glycine?

A

ion channel

(nAChR like)

57
Q

describe the subunit composition of the glycine receptor

A

5 subunits (two types, a and B)

always either (2xa and 3xB) or (3xa and 2xB)

each subunit has 4 TMDs

58
Q

where is the glycine binding site

A

on the a subunit

59
Q

what are the effects of glycine antagonists

A

convulsions (epilepsy)