Lecture 14 - GABAb Flashcards
What is special about GABAb?
-it is a GPCR that does not act alone
-always acts as couples or diads: GABAb1 and GABAb2
-GABAb1: needed for activation
-GABAb2: needed for signalling
What is the difference between GABAb1 and GABAb2?
-GABAb1 has the active site where GABA binds
-GABAb2 has the site that interacts with G-protein
What happens when GABA binds to the active site?
-one GABA binds to the GABAb1 receptor, which causes a conformational change in the GABAb2 receptor that allows the GABAb2 to interact with the G-protein
How does GABAb2 interact with the G-protein?
-alpha subunit acts as a Gi, inhibiting adenyl cyclase (AC), which leads to less cAMP
-cAMP is needed to activate PKA, and PKA is needed to phosphorylate our NMDA receptors
Why is it important for NMDA to be phosphorylated by PKA?
-important for NMDA receptor to be phosphorylated by PKA in order for the NMDA receptor to be functional
-if we don’t phosphorylate the NMDA receptor, a phosphatase is gonna come and strip off the phosphate group [PO4], leaving the NMDA inactivated
What is the difference between LGICs [GABAa] and GPCRs [GABAb]? (in terms of the membrane)
-GABAa: very quick immediate inhibition of the membrane by allowing Cl- ions in
-GABAb: signal amplified and more long-term effect because we are inactivating the excitatory receptors
What do the beta and gamma subunits do?
-beta and gamma subunits can phosphorylate [either directly or indirectly] voltage-gated Ca2+ channels (closing the channel)
-we downregulate the machinery that’s important for activating our NMDA receptors and we close our voltage-gated Ca2+ receptors
What are three ways that GABA, the neurotransmitter, inhibits neuronal transmission?
-acts on GABAa receptors, allowing more Cl- ions across the membrane [hyperpolarizing the membrane, preventing it from firing]
-acts on GABAb receptors, reducing activation of NMDA receptors via Gi inhibition of AC cAMP second messenger pathway.
-in axonal synapses, the beta-gamma portion of the G-protein can inhibit the voltage-gated Ca2+ channels. [preventing that neuron from releasing its neurotransmitter]
What is another big side effect of barbiturates other than the high abuse potential?
-they’re very memory-eroding
-sometimes, people forget the evening before when they take a higher dose
-similar side effect with alcohol too
What is the major drug that binds to the GABAb receptor system?
-GHB [also called liquid X] –> date rape drug (sometimes taken with ecstasy/MDMA)
-it is a very addictive compound
-side effects of GHB: from a little tipsy to suddenly really drunk; and frothing at the corners of the mouth
How is GHB linked to GABA?
-GHB can be synthesized from GABA and vice versa by the enzyme SSR [present in GABA neurons]
Where is GHB bound?
-most GHB is bound in the hippocampus, also in the cortex [but less], and in the hypothalamus [even less]. hippocampus > cortex > hypothalamus
-so it seems like there’s selective binding, as if GHB has a receptor to bind to
What does GHB do?
-it inhibits dopamine in motor areas of the brain [reduction in motor activity]
-the effects of GHB can be reversed by giving GABAb antagonists [effect of the drug are reversible]
[GHB has 10x the affinity to GABAb than GABA does]
Explain the mechanism of how GHB may block memories.
-if GHB is saturating our GABA receptor, now we’re downregulating PKA, therefore our NMDA receptors are no longer being phosphorylated.
–so they will lose that phosphate group and become inactive. [learning can’t happen with inactive NMDA]
-so memory never got encoded.
Describe & draw the entire mechanism of how GHB can block memory.
-Glu neuron, Glu is released
-there are AMPA and NMDA receptors on the post-synaptic neuron; also GABAb receptors
-GHB binds with high affinity to GABAb receptor –>activating GPCR –> alpha subunit reduces amount of cAMP being produced in neuron –> reduces PKA –> reduces phosphorylation of NMDA receptors [non-functional] [no memories]
