gaba

Question 1

what are different types of epilepsy seizures

Answer 1

partial (focal): simple and complex (loss of consciousness)

generalised: tonic-clonic (grand mal), absence (petit mal), febrile seizures, status epilepticus (life threatening), myoclonic

Question 2

what systems are involved in epilepsy

Answer 2

overactive glutamate system
underactive gaba syste
overactive sodium and calcium channels, underactive potassium channels

Question 3

what is the structure of gaba a receptors

Answer 3

they have 2 alpha and 2 beta and a fiftth subunit which varies

there are 6 types of alpha, 3 betas, 3 gammas, a delta, epsilon, pi and theta and rho1-3

Question 4

what are causes of epilepsy

Answer 4

disruption to ion channel function

dysfunctional receptor trafficking

Question 5

how are GABA a receptors trafficked

Answer 5

from the golgi body they are taken by vesicles to the membrane

Question 6

what mutations affect epilepsy at synaptic receptors

Answer 6

gamma2 R43Q is a mutation causing impaired assembly and trafficking of GABAa receptors

gamma2 K289M causes accelerated deactivation of GABAa receptors

alpha1 A322D causes reduced expression of receptors and reduced GABA potency, ER associated degredation

gamma2 Q351X causes loss of function/ trapped in ER

Question 7

how are GABAa receptors degraded

Answer 7

receptor is endocytosed in coated pit which has clathrin molecules attatched with AP2 adaptor on the end forming a proteosome

Question 8

what mutations affect GABAa extrasynaptic receptors

Answer 8

detla E177A reduces GABA currents

delta R220H reduces GABA currents

Question 9

what mutations affect the K/Cl cotransporter

Answer 9

L311H affects cotransporter function which pumps out chloride ions which flow through GABA receptor as well as intracellular potassium ions, reducing the membrane potential

Question 10

how is epilepsy treated with drugs

Answer 10

1st line:
phenytoin causes sodium channel block

carbamazepine causes na/ca channel block

ethosuximide causes ca channel block

valproate causes increased gaba levels/ ca channel block

2nd line:

gabapentin: ca channel blocker
felbamate: GABA potentiation
topiramate: GABA potentiation

Question 11

what is the effect of GABAb receptors and what type of receptor are they

Answer 11

they are GPCRs which either reduce presynaptic neurotransmitter release or bring about sustained inhibition of postsynaptic neuronal cells

Question 12

what roles do GABAb receptor play at different locations

Answer 12

they aid in cognition and LTP and the hippocampus, fear/aggression in the amygdala and nociception at the spinal chord

Question 13

where are GABAb receptors located

Answer 13

they are always located extrasynptically (in shafts of spines of dendrites pre and post synaptically, they are activated by spillover gaba

Question 14

what are targets of presynaptic GABAb receptors

Answer 14

voltage gated calcium channels: the beta gamma dimer of the GABAb receptor inhibits P/Q and N as well as T and L type channels, also reduces calcium concentration in terminal which inhibits pore formation and decreases neurotransmitter release

adenylate cyclase:
the alpha subunit (i/o) inhibits adenylate cyclase which reduces cAMP, PKA, disrupts PKA mediated phosphorylation of SNARE complex which retards vesicle priming

Question 15

what are postsynaptic receptor targets for GABAb

Answer 15

beta gamma complex activates GIRK 1 and 2 (potassium channels)

hyperpolarisation caused by potassium channels maintains mg block of NMDAR causing action potential failure

Question 16

descibe a compound synaptic current if glutamate and GABA receptors are activated

Answer 16

there is an early EPSP mediated by AMPA/KA followed by an early IPSP mediated by GABAa, this is sustained by GABAb creating a late IPSP, causing failure of NMDA current and action potential

Question 17

how are GABAb receptors formed

Answer 17

they form dimers, which must be hetero dimers (different types) for full function
receptor 1 or R1 binds agonists/antagonists

receptor 2 binds Gprotein and PAMs

different types of receptor R1a, R1b and R2, there cannot be 2 R1s

Question 18

describe GABAb subunit topology

Answer 18

contains 7TMH like GPCRs
contains a venus flytrap domain which is binding site for agonists

RSRR motif on R1 enable ER retention

there are sushi domains only on R1a

Question 19

where are the different GABAb types found

Answer 19

R1a/R2 is found presynaptically

R1b/2 is found postsynaptically

Question 20

what are agonists/antagonists used therapeutically for GABAb

Answer 20

agonist: baclofen is only ligand in clinical use, used to treat severe spasticity, neuropathic pain, migraine

competitive antag: phaclofen, saclofen used to treat cognitive disorders and experimentally to treat depression

positive allosteric modulator: many CGP compounds such as CGP7930 used to treat arthritic pain

Question 21

what function do presynaptic GABAbs have

Answer 21

control learning and memory through LTP, controls amount of glutamate release, prevents excitotoxicity

B1a (gene for R1a) knockout cannot discriminate between new and familiar, B1b and wild type can