Ligand gated ion channels 1 Flashcards
What are ligand-gated ion channels?
Multiple subunit proteins which form cation or anion channels.
What are the channel properties of ligand-gated ion channels determined by?
Subunit composition.
What does pentameric mean?
The receptor is made up of 5 different subunits.
What are the three types of GABA receptor?
GABAa, GABAb and GABAc.
What are the properties of GABAa channels?
It is a chloride ion channel, it’s agonist is GABA/muscimol, it’s antagonist is bicuculline and has an inhibitory cellular effect.
What are the properties of GABAb channels?
They are GPCR K+/Ca++ channels, their agonist is GABA/baclofen, the antagonists are saclofen/CGPs and they have inhibitory cellular effects.
What are the properties of GABAc receptors?
They are Cl- ion channels, their agonists are GABA/muscimol, their antagonists are TPMPA and they have inhibitory cellular effects.
What subunits are GABAa receptors made up of?
Two beta, two alpha and a gamma.
Where are the binding sites for GABAa receptors and how many are there?
Two - at the interface between alpha and beta subunits.
What is a cys-loop?
An extracellular region where the ligand binds.
Where do agonists bind?
At the N-terminal domain at the interface of alpha/beta subunits.
What happens when agonists bind?
There is opening of ion-selective pores (anion).
What conformational changes occur when ligands bind?
There is rotation of extracellular beta-sheets that are transmitted to the TM2 domain.
Do both agonist sites needed to be occupied?
For the channel to fully open - yes. Agonist binding increases the probability of the channel opening, two molecules binding will open it further and enhance the probability of it being open.
What is agonist affinity and efficacy altered by?
The alpha subunit.
What determines the agonist binding and activation to a channel?
Relative permeability, pore size and the presence of charged groups lining the pore.
What is different in the structure of the pore when it is open vs. closed?
The amino acid composition of pore is different in the activated vs. inactivated state.
What influence does the presence of different amino acids at the pore have?
Influences the ability of channels to be selective for different ions.
What action potentials do inhibitory synapses generate?
Inhibitory postsynaptic potentials (IPSPs).
How can the equilibrium potential for an ion be calculated?
Using the Nernst equation.
What are the two models of ligand binding/channel opening?
Induced fit model and the allosteric model.
What is the induced fit model?
Binding of an agonist to the receptor causes a conformational change in the ligand-binding site area which then propagates to the pore region to cause an opening of the ion-conducting pore.
What is the allosteric model?
The model depicting how the receptor is constantly undergoing spontaneous transitions between different conformations that confer different affinity for the ligand. The binding of an agonist stabilizes the channel in the open state.
How is GABA removed from the synapse?
Uptake through GABA transporters.
What are the four states in the kinetic model for GABAa receptors?
Closed (unbound), closed (bound), desensitized and open.
What is desensitization of GABA receptors altered by?
Endogenous factors (Zn, phosphorylation) and pharmacological agents (e.g. BZ). The effect of subunit composition is not well established.
How many different types of GABAa alpha subunits are there?
6
Where are alpha1 subunits found?
Widespread distribution in teh cortex, cerebellum and hippocampus.
Where are alpha 6 receptors found?
Only in the cerebellum.
