Chapter 3: Ion channels Flashcards
what ions do the most important ion channels regulate
calcium
sodium
chloride
potassium
what are ion channels made of
subunits of amino acids assembled around an ion channel
what 2 things regulate the sensativity of channel opening
neurotransmitters
allosteric modulators
structure of pentameric ionotropic receptors
5 subunits of 4 transmembrane regions
where are the receptor sites on each subunit
some are inside the channel and some are allosteric
Types of pentameric ionotropic receptors
GABAa receptors
Nicotinic cholinergic receptors
serotonin 5HT3 receptors
certain glycine receptors
neurotransmitters that act directly on pentameric ionotropic receptors
acetylcholine (nicotinic)
GABA (GABAa)
glycine (strychnine-sensative)
serotonin (5HT3)
natural neurotransmitters v. drugs on pentameric ionotropic receptors
neurotransmitters bind to every subtype and drugs may bind selectively to 1 or more subtypes
structure of tetrameric ionotropic receptors
4 subunits that contain 3 transmembrane regions and 1 entrant loop
where are the 4 re-entrant loops on tetrameric ionotropic receptors
they line the ion channel
types of tetrameric ionotropic receptors are
Glutamate receptors:
AMPA
Kainate
NMDA
action of full agonists on ionotropic receptors
open ion channel to max frequency for max downstream signal transduction
what increases opening of ion channel greater than full agonist
presence of a PAM
action of antagonist on ionotropic receptors
stabilizes receptor in its resting state (constitutive activity) despite the presence or absence of an agonist
what do antagonists reverse
full agonist
partial agonist
inverse agonist
action of partial agonist on ionotropic receptors
opens channel greater than constitutive activity but not as great as full agonist depending on how close it is to the full agonist/antagonist
action of an inverse agonist on ionotropic receptors
closes channel completely (less action than constitutive activity)
can inverse agonist be distinguished clinically from an antagonist
not clear
what are the different states of ionotropic receptors
desensitization and inactivation
what is desentiziation of an ionotropic receptor and what causes it
when the ion channel quits responding to the agonist over time due to over or prolonged stimulation.
quickly reversible
what is inactivation of an ionotropic receptor and what causes it
same as desensitization, however, it is one step past so it takes several hours after agonist is gone before it returns to its resting state and can again be stimulated by the agonist
what is an allosteric modulator
ligands that bind to sites other than where the neurotransmitters bind
what is a PAM and what does it do
positive allosteric modulator
when it binds to its allosteric site when the agonist is bound it increases the opening more than the full agonist alone
what is a NAM and what does it do
negative allosteric modulator
when it binds to its allosteric site while the neurotransmitter is bound it blocks or decreases the action of the neurotransmitter (agonist)
example of PAM
benzodiazepines
boost the action of GABA at chloride ion channels
example of NAM
NAM for NMDA:
phencyclidine
ketamine
when do allosteric sites have PAM action
when the ligand is a full agonist
when do allosteric sites have NAM action
when the ligand is an inverse agonist
which neurotransmitters work on pentameric ionotropic receptors
acetylcholine
GABA
serotonin
which neurotransmitters work on tetrameric ionotropic receptors
glutamate
examples of drug classes that act on GABA pentameric ionotropic receptors
benzodiazepines
Z drugs/hypnotics (zolpidem, zaleplon, zopiclone, eszopiclone)
neuroactive steroids
examples of drugs that act on serotonin pentameric ionotropic receptors
mirtazepine
vortioxetine
anti-emetics
example of drugs that work on glutamate tetrameric ionotropic receptors
PCP
ketamine
dextromethorphan
dextromethadone
what regulates opening of voltage-sensitive ion channels
the charge/voltage across the membrane
first phase of opening voltage-sensitive ion channel
voltage-sensitive sodium channels open and sodium rushes downhill into the negatively charged, sodium-deficient neuron
second phase of opening a voltage-sensitive ion channel
influx of sodium changes the voltage of the neuron which triggers the opening of voltage-sensitive calcium channels and calcium rushes in
third phase of opening a voltage-sensitive ion channel
once action potential is gone, potassium enters neuron and sodium is pumped out which restore electrical milieu back to baseline
what makes up the “pore” of VSSCs
when 4 amino acid subunits with sodium ionic filters come together to form the hole in the middle
what makes up the “pore” of VSCCs
when 4 amino acid subunits with calcium ionic filters come together to form the hole
what is the pore called on VSSCs
subunit a
what is the pore called on VSCCs
subunit a1
which transmembrane proteins flank subunit a (pore) of VSSCs and what do they do
B units and their function is not clearly established
how many transmembrane regions are on the amino acid subunits that make up VSSCs and VSCCs
6
which transmembrane segment detects the difference in charge across the membrane of voltage-sensitive ion channel subunits and why is that important
transmembrane segment 4
alerts the rest of the protein when it senses a change in charge which triggers conformational changes that open/close the channel
where is the extracelluar loop on voltage-sensitive ion channel subunits and why is it important
between transmembrane segments 5 and 6
functions as a filter to either allow sodium (VSSC) or calcium (VSCC) to enter
how are the subunits of voltage-sensitive ion channels connected
by connector loops
what is the significance of the connector loop between transmembrane units 3 and 4
act as a plug to close the channel
what are the three states of voltage-sensitive ion channels
open and active
inactivated
closed and inactivated
open and active state of voltage-sensitive ion channels
allow max flow of ions across the membrane
inactivated state of voltage-sensitive ion channels
loop goes into pore to stop the flow of ions immediately (before channel is even closed)
closed and inactivated state of voltage-sensitive ion channels
when there are conformational changes in the ion channels shape that closes it
what is the pore called on VSCCs
subunit a1
extracellular proteins that flank subunit a1
y (spans the membrane)
B (cytoplasmic units)
a2ẟ
pregabalin and gabapentin target which extracellular protein of VSCCs
a2ẟ
types of VSCCs
N or P/Q channels
L channels
R and T channels
N or P/Q channels of VSCCs
presynaptic regulators of neurotransmitter release
what is the “snare” in VSCCs
the amino acid loop that connects the 2nd and 3rd subunits work as a “snare” to hook to the synaptic vesicle to regulate the release of the neurotransmitter into the synapse during neurotransmission
how does the molecular “snare” work in N or P/Q voltage-sensitive ion channels
If a drug interferes with calcium entering the cell then the vesicle stays tethered to the channel and neurotransmission is prevented. When calcium enters the cell, the snare docks with the vesicles and moves it to the synapse so the neurotransmitter can spill into it.
how does the molecular “snare” work in N or P/Q voltage-sensitive ion channels
If a drug interferes with calcium entering the cell then the vesicle stays tethered to the channel and neurotransmission is prevented. When calcium enters the cell, the snare docks with the vesicles and moves it to the synapse so the neurotransmitter can spill into it.
what is another term for the work of the snare in N or P/Q voltage-sensitive ion channels
excitation-coupling
Where do L channel VSCC reside
in the CNS but also on vascular smooth muscle
R and T channel voltage-sensitive ion receptors
exact roles being clarified
some anticonvulsants and psychotropic drugs interact here
discuss ion channels and neurotransmission
neuron receives info from previous neuron and encodes it into an action potential.
the impulse is sent down the axon via VSSCs.
when the impulse reaches the axon terminal it meets VSCCs in the presynaptic membrane.
when the voltmeter in the VSCC detects the impulse they open to allow calcium into the neuron. Then neurotransmitter is released into the synapse
