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neuropharm > glutamate > Flashcards

glutamate Flashcards

1
Q

describe the difference in current produced between NMDA and AMPA receptor

A

AMPA produces a large, transient current, lasts 1-3ms

NMDA produces a current with less amplitude however is longer, lasts over 100 ms in zero mg
together they shape glutamate induced EPSPs
both allow sodium and potassium through, NMDAs and some AMPAs allow calcium

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2
Q

what normally plugs the NMDA receptor and what is its coagonist

A

coaognist: glycine
plug: magnesium

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3
Q

what are the different AMPA subunits

A

GluA1-4
GluA2 is a Q/R subunit standing for Gln/Arg; glutamine is changed to arganine RNA editing whist the other subunits undergo alternative splicing

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4
Q

describe the structure of the GluA2 subunit

A

it contains 4 transmembrane helices M1-4, the arginine residue is on M2, this arginine residue controls calcium permeability of receptor, these M2 helices face the inside of the pore

contains 2 extracellular binding domains D1 and D2 for agonist binding

like all AMPA subunits c terminus is intracellular and n terminus is extracellular

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5
Q

what feature makes AMPARs calcium permeable

A

they are calcium permeable if they lack GluA2

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6
Q

what are functions of CP-AMPARs

A

calcium permeable is CP

they are involved in post ischemic changes, motor neurone disease, hypoxic-ischemic white matter damage in early development, they are modulated by auxiliary subunit proteins

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7
Q

describe properties of CP ampars

A

they have high calcium permeability

they have an inwardly rectifying I/V relationship

high single channel conductance

they are blocked by intracellular spermine

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8
Q

when do polyamines block CP ampars and what role does this block have

A

when the cell is depolarised, positive charges on polyamine molecules repel cations

in synaptic plasticity it causes a switch from CP to CI AMPARs

in glial plasitcity it causes a switch from CI to CP AMPARs causing damage

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9
Q

what are the families of NMDA receptor and what are the NMDA subunits

A

NR1 or GluN1
NR2 or GluN2

GluN1 which has 8 different splice variants

GluN2A-D
GluN3A and B

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10
Q

what are functions of the NMDA receptor

A

involved in fast synaptic transmission

causes long term changes in synaptic responses

can cause excitotoxicity in excess activation since it leads to excessive calcium entry and degeneration of nerve cells

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11
Q

what are properties of the NMDA receptor

A

channel has a main conductance of 50pS although this is the a low conductance for the channel

magnesium ions bind to site within channel, which has voltage dependent release

channel has high calcium permeability which lead to long term changes in synaptic transmission

receptor is only active in presence of extracellular glycine EC50 is 50-300 nM

receptor is inhibited by protons, the IC50 proton concentration is pH 7.3 which is physiological pH

shows unusual kinetic behaviour

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12
Q

what main types of glutamate receptor are there

A

ionotropic: NMDAs, AMPAs, kainate and delta receptors

metabotropic gluRs

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13
Q

what are major roles of NMDA/AMPAs

A

NMDA: coincidence detection, development

AMPA: neurotransmission, plasticity mechanisms

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14
Q

what causes excitotoxicity

A

excessive and dysregulated activation of glutamate receptors

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15
Q

what are mechanisms of excitotoxicity

A

during excitation calcium increases intracellularly

this may lead to mitochondrial damage which leads to an increase in reactive oxygen species, nitric oxide, catabolic enzymes, pro-apoptotic factors and arachidonic acid, these lead to apoptosis/necrosis

the influx of calcium also causes further glutamate activation in a positive feedback loop

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16
Q

what is cerebral ischaemia

A

interruption of bloody supply (hypoxia, hypoglycaemia), leads to ATP/energy deficit and subsequent dissipation of ion gradients

can be focal or global

it is a stroke

cerebral ischeamia leads to energy depletion which leads to membrane depolarisation due to loss of ion gradient, which leads to large glutamate release which leads to cell death

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17
Q

describe the relationship between CP-AMPARs and ischemic injury

A

evidence of causal link between CPampars and ischemic injury

ischemic insults downregulate of GluA2 mRNA and trafficking

dysregulation of GluA2 RNA editing has been observed ischemia

GluA2 knockdown kills CA1 neurones while overexpression protects

CPAMPAR antagonists protected neurones in ischaemia

18
Q

what are therapeutic approaches to ischaemia

A

restore blood flow (alteplase)

iGluR antagonists neuroprotective in preclinical studies but have failed to live up to promise in clinical trials

xenon shows promise (blocks NMDARs at subanaesthetic doses)

CPAMPARs potential future target

19
Q

what is ALS

A

it is a neurodegenerative disease, caused by the degeneration and death of motor neurones, cognitive function is usually unaffected

20
Q

what is the excitotoxic model of ALS, and what is SOD1

A

SOD1 is a free radical scavenging enzyme abundant in the CNS, it is located in the cytosol and in the mitochondial intermembrane space

mutations in SOD1 are linked to familial ALS

expression of mutated SOD1 in transgenic rodents induce ALS symptoms

mutant astrocytes which usually transport glutamate out of glutamatergic synapses have inactive glutamate transporters resulting in a toxic amount of glutamate at the synapse

21
Q

what is the relationship between glutamate and ALS

A

motor neurones are hyperexcitable in presymptomatic ALS

CSF glutamate levels are increased in 40% of sporadic ALS patients

astrocyte glutamate uptake deficient in ALS patients

D-serine levels are also increase due to NMDA activation, D serine is an NMDA coagonist

22
Q

why is ALS pathology selective for motor neurones

A

spinal mns receive strong glutamatergic input

they have low calcium buffering capacity

they express CP-AMPA receptors

23
Q

how do CP AMPARs relate to ALS

A

low GluA2 mRNA in motor neurones

GluA2 knockout accelerates motor neurone degeneration in SOD1 mutant mice

replacement of GluA2 will increase life span

ALS patients show reduction in GluA2 editing efficiency in MNs

CP-AMPAR blocker protective in model system

24
Q

what are therapeutic approaches to ALS

A

riluzole has been licenced, it is a general inhibitor of glutamatergic transmission, it inhibits sodium channels and enhances clearance of glutamate from synapse

targeting glutamate transport more directly is yet to be validated

CP-AMPAR antagonists

SOD1 antisense oligonucleotides

25
Q

what cause positive and negative symptoms in schizophrenia

A

positive symptoms are caused by overactivity of the mesolimbic pathway between the ventral tegmental area and the nucleus accumbens

negative symptoms and cognitive symptoms are caused by mesocortical pathway dysfunction between the vental tegmental area and the prefrontal cortex

26
Q

how does glutamate relate to schizophrenia

A

a proposition is that NMDA hypofunction is key to pathology

NMDAR antagonists PCP and ketamine mimic and exacerbate schizo symptoms

reduced NMDAR expression results in symptoms resembling schizophrenia

post mortem studies showed altered iGluR gene expression in schizo patients

gene associations linked to glutamatergic transmission

27
Q

how is schizophrenia treated therapeutically

A

current antipsychotics target dopamine (D2) and 5HT systems but also other NTs

around 30% of patients are treatment resistant

mGluR agonists are effective in treatment

ampakines may be useful adjunct therapy for treatment of cognitive deficits (positive allosteric modulator of AMPA receptor)

28
Q

how can iGluRs be used to treat depression

A

there are altered levels of glutamate in depression

iGluR expression and function are dysregulated in depression

current antidepressants can modulate iGluRs

NMDAR antagonists have positive therapeutic benefits

ketamine may be used as an antidepressant (NMDAR antagonist), esketamine approved for treatment

29
Q

how is epilepsy treated

A

in general to enhance GABAa receptors via benzodiazepines

inhibit sodium channels (phenytoin)

inhibit calcium channels (gabapentin)

perampanel used to block AMPA receptor via noncompetitive inhibition

valproate used to block NMDA receptors as well as increase GABA turnover and block sodium channels

topirmate and felbamate both block sodium channles and increase GABAa receptor activity, t blocks AMPA/kainate receptors, felbamate blocks NMDARs

30
Q

what are the different mGluRs and what families are they in

A

group one: MgluR 1 and 5, increases PLC for signal transduction (phospholipase C)

group 2: includes 2 and 3, decreases adenyl cyclase

group 3 includes: 4 and 6-8 decreases adenyl cyclase

31
Q

how do mGluRs compare in size to other receptors, and what is there structure

A

they are large when compared to other GPCRs

they form dimers, and have a “venus flytrap module” of binding

32
Q

what are agonists and antagonists of mGLurS

A

agonist: glutamate, ACPD
antagonist: mcpg

33
Q

what are the different subunits of mGluRs

A

20 types of alpha subunit
6 types of beta subunit
11 types of gamma subunit

if all combinations are permissible leads to over 1000 combinations

34
Q

what is the plc GPCR pathway

A

agonist binds to receptor and affinity for G protein trimer increases

binding of G protein trimer reduces binding affinity for GDP and GTP replaces GDP on trimer, which activates it

when GTP is bound the alpha subunit dissociates from beta-gamma dimer

alpha and beta-gamma bind to effectors and activate them, alpha subunit has intrinsic GTPase activity, after GTP is hydrolysed to GDP affinity for betagamma subunit is increased

35
Q

what affect does ACPD/glutamate have on postsynaptic currents

A

they block voltage gated potassium channels, blocking the after hyperpolarisation period

36
Q

what is a presynaptic action of ACPD

A

in hippocampus slice of CA1 region ACPD depresses synaptic transmission by decreasing presynaptic neurone voltage

37
Q

how is mGluR1 spread

A

it is located perisynaptically (around the edge) as opposed to the middle

38
Q

what are actions of mGLurs at diffferent locations in pain

A

ventrobasal thalamus: group 1 mglurs process thermal nociception

amygdala: plays a part in emotive content of stimuli involves mglur 1 and 5

spinal chord: group 1s are located postsynaptically and are pro nociceptive

group 1 antagonist can reduce wind up associated with hyperalgesia

groups 2 and 3 are located presynaptically, activation of group 2 can selectively block nociceptive but not sensory transduction

peripheral: mglur 1/5 are located on sensory terminals of pain fibres

39
Q

what is an allosteric modulators of mglurs

A

ro 67-7476 is a positive allosteric modulator of mglurs, allosteric binding site is deep in the transmembrane domain

40
Q

what is an example of an allosteric modulator used in therapy

A

PhCCC is used in treatment of parkisons, and reverses reserpine induced akinesia, protects against MPTP toxicity, is a positive allosteric modulator of mglur4 and an agonist of 6

the striatopallidal inhibitory pathway is overactive but can be quietened down by agonists active at mGluR4 in parkinsons

41
Q

how does mglurs affect fragile x syndrome

A

fmr1 gene disrupted codes for fragile x mental retardation protein which is essential for normal cognitive development, hyperactive mglu5 pathways

neuropharm (4 decks)

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