PHYSL 371: Ligand gated ion channels

where are ligand gated ion channels present

at the synapse

3 types of ligand ion channels

1. P2X receptor like family

2. Cys-loop (nicotinic receptor like family)

3. GluR (glutamate receptor like family)

what does Po depend on for ligand gated channels

the binding of a molecule (ligand/agonist) to the receptor on the channel

what is the relationship between activation and agonist concentration

sigmoidal relationship where the level of activation increases with increased ligand concentration

miniature post synaptic potentials (minis)

random spontaneous release of NT vesicles which activate inotropic receptors in single synapses that result in small currents

evoked post synaptic potentials

spontaneous release of many synaptic vesicles at once due to the experimentally triggered stimulation of the presynaptic cell

inotropic glutamate receptors

non-selective cation channels (Na+, K+ and sometimes Ca2+) where glutamate is the physiological agonist for all subtypes

what is the nernst potential for iontropic glutamate receptors

the average RP for all the ions it conducts which usually falls around 0mV

what are the 2 subtypes of glutamate receptors

1. NMDA receptors

2. non-NMDA receptors

what are the two types of non-NMDA receptors

AMPA and Kainate

what is the physiological agonist of NMDA and non-NMDA receptors

glutamate

what are the pharmacological against of NMDA and non-NMDA receptors

AMPA and NMDA

what is the structure of ionotrpic glutamate receptors (iGluR)

upside down K+ channels composed of 4 subunits (tetrameric) with a selectivity filter in the membrane bound region and a ligand binding domain (LBD) on the extracellular side

what does the LBD control

opening and closing of the channel

what ions are AMPA receptors permeable to

Na+ and K+ primarily

what genes encode AMPA receptors

GluR1, GluR2, GluR3, and GluR4

what happens when glutamate binds to an AMPA receptor

it will rapidly densensitize

what happens when AMPA binds to an AMPA receptor

it will rapidly densensitize

what happens when kainate binds to an AMPA receptor

it will not desensitize

what part of the conductance equation changes with desensitization

Po will decrease as sensitization decreases resulting in a smaller conducatnce

what are the 4 types of AMPA receptors

1. GluRA (or 1)

2. GluRB (or 2)

3. GluRC (or 3)

4. GluRd (or 4)

what are kainate receptors permeable to

Na+ and K+

what genes encode kainate receptors

GluR5, GluR6, GluR7, KA1, KA2

what combination of genes is needed to code a kainate receptor

at least one of the GluR genes to be able to use a KA gene

what happens when glutamate binds to a kainate receptor

it will desensitize

what happens when kainate binds to a kainate receptor

it will desensitize

what happens when AMPA binds to a kainate receptor

it will not be responsive

what are NMDA receptors permeable to

Na, K, Ca

what happens when NMDA channels are triggered

they will allow for prominent Ca2+ influx which can trigger diverse cellular responses

what are 3 things Ca2+ influx can trigger

1. developmental actions

2. learning and memory (ex. LTP)

3. excitotoxicity if activity is too high

2 types of NMDA receptors

1. homomeric receptors

2. heteromeric receptors

what are the 4 types of NR2 subunits

1. NR2A

2. NR2B

3. NR2C

4. NR2D

homomeric receptors

very small glutamate gated currents that are only NR1

heteromeric receptors

combination of NR1 and NR2 (or NR3) that produce large currents and are the main receptor in the brain

what do heteromeric receptors need for activation

they require glutamate as their agonist and glycine as a co-agonist

what acts as a competitive antagonist for heteromeric receptors

APV

what do the different NR2 subunits do

confer different properties like a Mg2+ voltage dependent block

what does the ability for NMDA receptors to be active depend on

the voltage a cell is at

when do NMDARs conduct the most

at positive membrane voltages

what happens to glutamate receptors at positive membrane potential voltages

NMDA receptors contribute the most by having long sustained outward current that allows Ca2+ to exit the cell

what happens when you add APV at positive membrane voltages

the current does not last as long because NMDA receptors are blocked

what happens to glutamate receptors at negative membrane potential voltages

AMPA receptors contribute the most by having a large inward current

what happens when you add APV at negative membrane voltages

NMDA receptors do not really contribute at negative membrane voltages therefore blocking them won't cause a large effect

why do NMDAR not conduct well at negative membrane potentials

Mg2+ blocks the channel even when it is opened by glutamate

what happens to NMDAR when the cell is depolarized

Mg2+ exits the pore and the channel is able to conduct again

what is the pattern of AMPAR currents

early and fast

what is the pattern of NMDAR currents

late and slow

what happens between glutamate receptors when voltages become more positive than -80mV

the Mg2+ ion leaves the pore and the NMDA current becomes significant and lasts much longer than the AMPA current

The GABAa receptor

major ligand-gated inotropic channel receptor in the CNS

what is the GABAaR permeable to

Cl- ions

what is the structure of GABAaRs

pentameric heterooligomer (5 subunits come together to form the channel)

reversal potential for Cl-

-60 to -70 mV

what happens when a GABAaR is activated

Cl- will flow out of the cell until its RP is met but then will stop flowing out any further therefore not allowing the cell to reach threshold

GABAaR agonists

GABA, muscimol

GABAaR antagonist

bicuculline

GABAaR channel blocker

picrotoxin

what else does picrotoxin block

glycine receptor chloride channels

how many combinations of GABAaR are there

the theoretical number of subunit permutations is enormous leading to a large variety of possible combinations

what are the 5 main subunits that make up a GABAaR

1. alpha

2. beta

3. alpha

4. beta

5. gamma

how many GABA binding sites are there per channel

2

where are the 2 GABA binding sites located

in between both alpha and beta subunits

what is the direction of Cl- current when the membrane potential is held at negative voltages

the reversal potential of Cl- will be more positive therefore Cl- will flow out of the cell, making it more positive (INWARD CURRENT)

what is the direction of Cl- current when the membrane potential is held at positive voltages

the reversal potential of Cl- will be more negative therefore Cl- will flow into the cell, making it more negative (OUTWARD CURRENT)

what determines the direction of current or voltage change

the relationship between the Nernst/reversal potential of the conduction ion and the membrane potential

what are some examples of benzodiazepines

tranquilizers, hypnotics, anxiolytic, antipanic, and anticonvulsants

what do benzodiazepines do

increase the affinity for GABA to GABAaR leading to increased frequency of channel opening and potentates the effects of GABA

what do benzodiazepines require in order to work

it requires GABA agonist to bind as well to the channel as it binds

what type of modulator are benzos

positive (increase GABAs effectiveness) Allosteric (binds to a different site than GABA) modulator

(PAM)

what binding site does GABA bind to

at the interface in between the alpha and gamma subunits

what is the difference between two samples with the same concentration of GABA but one has benzos

the one with benzos will produce a greater effect

what are Bezos used for

to suppress excitability