GABARs: Dynamics of inhibition in health and disease

Question 1

What is Gephyrin analogous to? Where is it found?

Answer 1

PSD-95

Found in inhibitory synapses (mostly)

Question 2

What are two ways GABAARs are modulated by CaMKII?

Answer 2

1) It phosphorylates the beta and gamma subunits at specific residues, either prolonging duration of opening, or increasing amplitude of response (via a trafficking of more receptors to the synapse)

Question 3

How is Calcium relevant to GABAR homeostasis? What protein helps with this?

Answer 3

Important in a homeostatic loop tha tmakes sure GABAR espression is fine tuned to give the expected response

Gephyrin buildup/breakdown is also important in this cycle

Question 4

How can GABARs modulate their response in a way that GluRs can’t?

Answer 4

By using ion channels to regulate the concentration of Cl-

GluRs can’t do this because Potassium Conc needs to be highly regulated

Question 5

What pumps are involved in Cl balance?

Answer 5

NKCC1 bring Cl into cells during development

KCC2 brings Cl out

Question 6

Why do GABA channels depolarize newborn neurons?

Answer 6

There isn’t enough Cl in the cell yet (NKCC1 hasn’t kicked in yet)

Question 7

Why do you only feel pain when you’re injured?

Answer 7

Light touch normally sends a pain signal down the C fibre via GluRs but it’s constantly inhibited by GABARs

Injury removes the inhibition via NKCC1 and KCC2

Question 8

What are neurosteroids? Where are they located and in what concentrations?

Answer 8

Steroids that can act on the brain

Circulating in blood at the nanomolar level (very potent)

Question 9

Where are neurosteroids made? From what?

Answer 9

In the mitochondria, from cholesterol

Question 10

How do neurosteroids work?

Answer 10

Released by glial cells, bathe the synapse and activate extrasynaptic receptors

This allows for phasic and tonic control of GABA response

Question 11

Where do neurosteroids bind on the GABAR? Once bound, how to they function mechanically?

Answer 11

In the TMD, depending on whether or not they positively or negatively modify the receptor they either assist the pore twisting open or prevent it from opening

Question 12

How do neurosteroid levels change during development?

Answer 12

Huge spike during birth, drop off after development, very low circulating levels during adulthood

Question 13

What are neurosteroids implicated with? How?

Answer 13

Stress
Different GABARs in the brain operate the neurocircuit of stress
Neurosteroids regulate these receptors

Question 14

What disease is often associated with GABA channelopathies?

Answer 14

Epilepsy

a single point mutation is often enough