Ch 6 - Ligand-Gated Ion Channels of Fast Chemical Synapses

complete

where are ligand gated ion channels expressed?

in all cell types

are ligand-gated channels selective?

generally, no

ligand channels produce ___ (in relation to AP firing)

generator potentials necessary to open voltage-gated channels

ligand gated channels are most structurally similar to

K+ channels (they require multiple subunits to form a channel)

nicotinic family: how many subunits/transmembrane segments?

5 subunits, 4 transmembrane segments

Glutamate family: how many subunits/transmembrane segments?

4 subunits, 3 transmembrane segments

P2X family: how many subunits/transmembrane segments?

3 subunits, 2 transmembrane segments

which ligand gated channels are trimeric?

P2X

which ligand gated channels are tetrameric?

glutamate family

which ligand gated channels are pentameric?

nicotinic family

ATP channels are an example of

P2X

AMPA receptors and NMDA receptors are examples of

glutamate receptors

nicotinic receptors, serotonin receptors, and GABA A receptors are examples of what kind of channel?

nicotinic receptors

ligand gated ion channels respond to ___ to generate ___

respond to neurotransmitters to generate postsynaptic potentials

stimulation of motor neurons releases

acetylcholine

describe how a post-synaptic potential is produced at the neuromuscular junction.

stimulation of motor neuron causes release of NT (ACh)

ACh binds to ACh receptors on muscle

opening of ACH-gated ion channels generates depolarization due to cation influx

farther away from motor neuron → ___ depolarization

smaller

which of the following could not be a multimeric channel made up of different alpha subunit subtypes? nAChR, AMPA, GABA, vg-K+ channel, vg-Ca2+ channel

vg-Ca2+ channel because the rest are made of multiple subunits

how are nicotinic and muscarinic acetylcholine receptors differentiated?

nicotinic ACh receptors respond to nicotine, muscarinic ACh receptors are G-protein coupled

where are nACHRs found?

neuromuscular junction, autonomic ganglia, and throughout the nervous system

nACHRs are involved in…

movement, cognition, perception, attention, depression, pain, reward

what ions are nACHRs permeable to?

Na+, K+, and sometimes Ca2+

nAChRs are (excitatory/inhibitory)

excitatory

nACH receptor agonists

nicotine, varenicline, carbachol, galantamine

nACh receptor antagonists

curare/pancuronium, buproprion

ACh is degraded by

acetylcholinesterases

acetylcholinesterase inhibitors

Donepezil, pesticides, chemical warfare agents

inhibitors of acetylcholinesterases are used for treatment of

alzheimers

describe nAChR structure

5 subunits (2 are alpha, the other 3 vary). the channel has an extracellular domain, a transmembrane domain, and an intracellular domain

once ligand gated channels are open, they generate currents that are sensitive to

voltage

how does amplitude of the current change depending on the holding voltage?

more hyperpolarized → larger current

ligand gated ion channel reversal potential

around 0 (due to being non-selective)

how do you calculate the reversal potential for a channel that is permeable to sodium and potassium?

Vmrev = [nernst + nernst]/2

= (+67 + -98)/2

= -31/2

= -15.5

Erev changes at every ___. why?

it changes at every synapse. this is because the extra- and intra-cellular concentrations change

Activation curve is a ___ curve where response is ___.

concentration-response curve

current amplitude

ligand gated ion channels exist in multiple states that are influenced by whether ___ is bound

ligand/agonist

receptor is ___ when unbound

closed

agonist binding promotes the ___ state of channels

open

what is an A burst?

the period of time where a channel is mostly open, but closes briefly

openings of LGICs cause ___ that add up to ___

small depolarizations, reach threshold

what is this graph showing?

small depolarizations adding up to threshold, where you start to see APs.

C is magnified view of B, showing how binding/unbinding of agonist causes channel openings/closings that result in the depolarization cycles

how are ligand-gated channels different than voltage-gated channels in terms of the process of gating?

ligand-gated requires a conformational change instead of a voltage sensor moving in response to voltage.

when an LGIC opens, the rotation of channel subunits breaks ___ that are blocking the pore.

hydrogen bonds

what determines the cation specificity of nACh receptors? what else does it do?

rings of high negative charge on the cytoplasm side. these also remove the hydration shell of the passing ions

which kinds of receptors make up the nicotinic/cys-loop superfamily? (4)

nACh receptors

GABA receptors

Glycine receptors

Serotonin/5-HT₃ receptors

what is a cys-loop and what does it do?

cysteine-cysteine disulfide bond. it participates in ligand binding.

which transmembrane domain typically lines the pore in cys-loop receptors?

M2

where is the agonist binding site on a cys-loop receptor?

near the cys loop (extracellular)

how are GABA_A, GABA_B, and GABA_C different?

GABA_A and GABA_C are ligand-gated

GABA_B is G-protein coupled

ion channels on GABA receptors are selective to what ions?

Cl^- and HCO₃^-

GABA receptors have a ___ effect on neurons. why?

inhibitory/hyperpolarizing effect. this is due to the Cl- entering the cell

___ subunits form homomers (GABA_C receptors) in the retina

ρ

GABA receptors are ___ (structure). what subunits?

pentamers.

alpha and beta + a combination of γ/δ/π/ε to make a pentamer

GABA_A agonists

GABA, muscimol

GABA_A antagonists

competitive: bicuculline and flumazenil

noncompetitive: picrotoxin

what do positive allosteric modulators do?

increase agonist affinity and/or efficacy

what are the five types of positive allosteric modulators for GABA_A receptors?

Benzodiazepines

non-benzodiazepines that bind at the benzo site

Barbiturates

Anesthetics

Ethanol

what neurosteroids affect GABA_A receptors?

negative: pregnenolone

positive: allopregnanolone

what do these graphs show?

A shows the opening and closing of GABA channels in response to agonist binding. B shows the influence of pentobarbital, a positive allosteric modulator.

→ even though barbiturates don’t directly open the channel, they modulate the channel in a positive way, increasing the activation

Opening of GABA-gated Cl- channels can cause

excitation

(increasing cellular Cl- makes the nernst more positive for Cl-. under these conditions, opening Cl channels will depolarize neuron.

what transmitter/associated receptor has a prominent impact on the developing brain?

GABA

in developing neurons, the intracellular Cl- concentration is controlled by ___, resulting in ___ intracellular levels of Cl-

the Na+/K+/Cl- co-transporter, resulting in high intracellular levels of Cl-

in adult neurons, the intracellular Cl- concentration is controlled by ___, resulting in ___ intracellular levels of Cl-

K+/Cl- (which pumps Cl- out of cell), results in low intracellular Cl- levels

if GABA is selective to Cl- ions and is considered an inhibitory neurotransmitter, why does it have an excitatory effect in the developing brain?

E_Cl- changes. In development, E_Cl- is more positive than AP threshold and the intracellular concentration of Cl- is high. Cl- moves out of GABA receptors, depolarizing response.

In adult cells, E_Cl- is much more negative and intracell Cl- concentration is low. Cl- moves into the cell, hyperpolarizing response.

___ GABA receptors mediate phasic inhibition while ___ GABA receptors mediate tonic inhibition

synaptic, extrasynaptic

what are GABA transporter proteins called?

GAT-1

which GABA alpha subtype(s) cause sedative, anterograde amnesia, and anticonvulsant effects?

α1

which GABA alpha subtype(s) cause anxiolytic and muscle relaxant effects

α2 and α3

which GABA alpha subtype(s) cause cognitive effects?

α5

the goal for an anxiety drug is to bind to which α subtype(s)?

α2 or α3, but not α1 (α5 is also not desirable)

the goal for a sedative is to bind to which α subtype(s)?

α1 (α5 not desirable)

glycine receptors are selective to which ion channels?

Cl-/HCO₃^-

glycine receptors have a(n) ___ effect on neurons

inhibitory, hyperpolarizing

glycine agonists (5)

glycine

β- or L-alanine

taurine

L-serine

proline

Glycine positive allosteric modulators (3)

anesthetics, neurosteroids, ethanol

Glycine negative allosteric modulator

strychnine

what are subconductance states?

states other than open or closed

define EPSP and IPSP

EPSP - excitatory postsynaptic potential

IPSP - inhibitory postsynaptic potential

EPSPs result from stimulation of ___, releasing what transmitter?

stimulation of sensory fiber releasing glutamate

IPSPs result from stimulation of ___, releasing what transmitter?

inhibitory interneuron, releasing glycine

GABA and Glycine are ___ transmitters found in…

both inhibitory

GABA - throughout CNS

Glycine - brainstem and spinal cord

5-HT3 serotonin receptors are selective to which ions?

non-selective for Na+, K+, Ca2+

5HT3 receptors have a ___ effect on neurons

excitatory, depolarizing effect

serotonin receptor agonists

serotonin, quipazine

serotonin receptor antagonists

ondansetron, granisetron, tropisetron (antiemetics)

what receptors are in the “vomiting center” within the pons?

5-HT3, NK1, dopamine

glutamate receptors differentiated by 

response to NMDA, AMPA, and Kainate

each subunit of a glutamate receptor has ___ transmembrane segments and a ___ loop. how many subunits make up a channel?

3 TM segments, P-loop. 4 subunits make up a channel

GluR1-4

AMPA channels

GluR5-7

Kainate channels

NMDA receptors are permeable to which ions?

Na+, K+, and Ca2+

NMDA receptors are coactivated by

glycine and serine

NMDA antagonists

phencyclidine (PCP), ketamine, dextromethorphan, memantine, riluzole

NMDA is blocked by what ion? how is it unblocked?

blocked by Mg2+, requires depolarization to unblock

Glycine is an NMDA co-agonist at ___ channels. D-serine is an NMDA co-agonist at ___ channels

extrasynaptic, synaptic

activation of NMDA receptors requires depolarization of

AMPA or other receptors

describe the activation of NMDA receptors

depolarization removes Mg2+ from pore → ions can flow through channel

AMPA receptors are permeable to

Na+ and K+

AMPA/Kainate receptors have a ___ effect on neurons

excitatory, depolarizing effect

AMPA agonists

AMPA > glutamate > kainate