glutamate Flashcards
describe the difference in current produced between NMDA and AMPA receptor
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
what normally plugs the NMDA receptor and what is its coagonist
coaognist: glycine
plug: magnesium
what are the different AMPA subunits
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
describe the structure of the GluA2 subunit
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
what feature makes AMPARs calcium permeable
they are calcium permeable if they lack GluA2
what are functions of CP-AMPARs
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
describe properties of CP ampars
they have high calcium permeability
they have an inwardly rectifying I/V relationship
high single channel conductance
they are blocked by intracellular spermine
when do polyamines block CP ampars and what role does this block have
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
what are the families of NMDA receptor and what are the NMDA subunits
NR1 or GluN1
NR2 or GluN2
GluN1 which has 8 different splice variants
GluN2A-D
GluN3A and B
what are functions of the NMDA receptor
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
what are properties of the NMDA receptor
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
what main types of glutamate receptor are there
ionotropic: NMDAs, AMPAs, kainate and delta receptors
metabotropic gluRs
what are major roles of NMDA/AMPAs
NMDA: coincidence detection, development
AMPA: neurotransmission, plasticity mechanisms
what causes excitotoxicity
excessive and dysregulated activation of glutamate receptors
what are mechanisms of excitotoxicity
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
what is cerebral ischaemia
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
describe the relationship between CP-AMPARs and ischemic injury
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
what are therapeutic approaches to ischaemia
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
what is ALS
it is a neurodegenerative disease, caused by the degeneration and death of motor neurones, cognitive function is usually unaffected
what is the excitotoxic model of ALS, and what is SOD1
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
what is the relationship between glutamate and ALS
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
why is ALS pathology selective for motor neurones
spinal mns receive strong glutamatergic input
they have low calcium buffering capacity
they express CP-AMPA receptors
how do CP AMPARs relate to ALS
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
what are therapeutic approaches to ALS
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
what cause positive and negative symptoms in schizophrenia
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
how does glutamate relate to schizophrenia
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
how is schizophrenia treated therapeutically
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)
how can iGluRs be used to treat depression
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
how is epilepsy treated
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
what are the different mGluRs and what families are they in
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
how do mGluRs compare in size to other receptors, and what is there structure
they are large when compared to other GPCRs
they form dimers, and have a “venus flytrap module” of binding
what are agonists and antagonists of mGLurS
agonist: glutamate, ACPD
antagonist: mcpg
what are the different subunits of mGluRs
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
what is the plc GPCR pathway
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
what affect does ACPD/glutamate have on postsynaptic currents
they block voltage gated potassium channels, blocking the after hyperpolarisation period
what is a presynaptic action of ACPD
in hippocampus slice of CA1 region ACPD depresses synaptic transmission by decreasing presynaptic neurone voltage
how is mGluR1 spread
it is located perisynaptically (around the edge) as opposed to the middle
what are actions of mGLurs at diffferent locations in pain
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
what is an allosteric modulators of mglurs
ro 67-7476 is a positive allosteric modulator of mglurs, allosteric binding site is deep in the transmembrane domain
what is an example of an allosteric modulator used in therapy
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
how does mglurs affect fragile x syndrome
fmr1 gene disrupted codes for fragile x mental retardation protein which is essential for normal cognitive development, hyperactive mglu5 pathways
