LEC16: Ligand-Gated Channels Flashcards
what differentiates channels, by structure, from carrier proteins?
1) contain a water-filled pore through which ions travel, **strictly down electrochemical gradienst **
2) don’t bind solutes to be transported
3) don’t operate in cycles
4) DO undergo conformational changes to toggle btwn open and closed states
what regulates most channels?
first messengers- extracellular signals, including hormones, neurotransmitters, odorants, air pressure (sound waves), photons (acting on visual cells)
what kind of modulation do ligand-gated channels do?
what do they mediate?
where do they usually operate?
what are 2 examples?
ligand-gated channels (aka ionotropic receptors) do direct modulation by a signaling molecule
mediate r**apid cell-cell communication **
incorporate a channel in a protein that also incudes the receptor, which is usually a hormone or neurotransmitter
when signaling molecule binds receptor, induces a conformational change that opens the channel
present in signaling btwn neurons &transmission from neurons to skeletal muscle cells
eg: cys-loop channels/receptors & glutamate receptors
where do most ligand-gated channels occur?
at a synapse, either btwn neuron-neuron or neuron-muscle cell
what does an **excitatory **stimulus do to a membrane? how do they work?
**depolarizes **the membrane by activating an inward current or reducing an outward current
what does an **excitatory channel **carry?
inward currents
what does an inhibitory stimulus do to the membrane? how?
hyperpolarizes the membrane
increases K+ conductance or activates Cl- conductance
what is hyperpolarization? depolarization?
**hyperpolarization: **if the inside becomes more negative than the outside
**depolarization: **inside becomes less negative than the outside
what is capacitance?
membrane property - the ability to restore charges in the membrane, in response to a current
what is the **effect of capacitance **on Vm?
membrane tends to ignore events that are brief
??
what is the reversal potential?
**reversal potential **of an ion: membrane potential at which there is no net (overall) flow of that particular ion from 1 side of teh membrane to the other
reversal potential = equilibirum potential in a single-ion system
are ligand-gated channels selective for a particular ion?
what’s the effect of this on reversal potential?
b/c they’re ion channels, most aren’t very selective for ions they conduct
therefore, currents that flow thru often are carried by more than 1 ion species
therefore reversal potential for the current is determined by the channel’s relative conductances for the participating ions
what is the structure of Cys-Loop channel receptors?
loop in extracellular N-terminal domain formed by Cys-Cys bridge - where ligand binds to produce conformational chagne in channel
heteromeric or homomeric pentameters (5 subunits)
each subunit has 4 TM spanning helices (M1-4)
large intracellular loop btwn M3-M4 that associates with cytoskeletal partners
walls are formed by five M2 helices
channels are selective for either cations or anions; otherwise, non-discriminating
what are examples of Cys-Loop channels?
1) nAChR, nicotinic acetylcholine receptor
2) GABA-A, gamma-aminobutyric acid receptor
what is significant about the different subunits of a Cys-loop channel?
there are different types of the 5 subunits (alpha-gamma)
depending on if in a muscle cell, neuron in brain, neuron in ANS, will have different complements
**ALL functional channels have at least 2 alpha subunits b/c ACh binds at interface btwn alpha and another subunit **
what is the nature of the residues lining the outer regions of the nAChR pore?
what is the nAChR channel selective for?
what are the extracellular binding sites in the nAChR channel?
what is the reversal potential?
are ions that pass through hydrated or dehydrated?
rings of negatively charged residues line pore
thus permeable to cations, primarily Na+ (inward) and K+ (outward), but also Ca2+ and Mg2+
extracellular ACh binding sites formed by alpha-delta and alpha-gamma interfaces
reversal potential: 0 mV
ions that pass through can be hydrated
what is the “gate” of the ligand gated channel?
region where conformational change occurs to change conductance
what is nAChR’s gating model/mechanism? how does it work?
in closed state, kink in M2 helices projects into pore, forming barrier composed of ring of hydrophobic residues
when both M2 are bound by ACh, M2 helices rotate away from center, pore is opened, permits current flow
get very fast channeling through
what is the structure of the GABA-A channel’s residues?
what does the GABA-A channel select for?
what does it mediate?
what is the reversal potential?
ligand-gated channel, like nAChR
however, basic residues in center so **selects for anions (Cl-) only **
has binding site for the nt GABA, gamma-aminobutyric acid
reversal potental = -80 mV
mediates fast inhibitory transmission in the brain
what activates glutamate receptors?
what are the types of glutamate receptors?
what are they permeable to?
what do they mediate?
activated by glutamate, excitatory neurotransmitter
**AMPA-type & NMDA-type **
permeable to **Na+, K+, Ca2+ **
mediate fast synaptic transmission in the brain
what is the transmembrane structure of glutamate receptors?
what is their selectivity filter?
**3, tetramers **of subunits (TM1-3) in TM region
selectivity filter is a **re-entrant loop **on the cytoplasmic side
what is the AMPA-type glutamate receptor selective for? what is its reversal potential?
selective for Na+ and K+
reversal potential is ~0 mV
what is the NMDA type glutamate receptor permeable to? what is its reversal potential?
permeable to Ca2+, Na+, K+
reversal potential = ~ +20 mV
how do both the NMDA and AMPA-type glutamate receptors’ gating mechanisms work?
what is the difference in their fxn?
glutamate binds, opens the channel
both are permeable to Na+ and K+
**however, NMDA type: has GluN subunits; is blocked at resting membrane potential by Mg2+ from the outside; so must bind extracellularly co-transmitter, Gly, for opening **
what is the interaction between AMPA- and NMDA- type glutamate receptors? how does one help the other open up? describe the process
1) glutamate is released into synapse by a presynaptic neuron
2) glutamate crosses synapse, binds to, activates AMPA receptors, depolarizing postsynaptic neuron
glutamate also binds to NMDA receptors and opens their channel gates, but Mg2+ ions block NMDA channels
3) surge in synaptic glutamate from presynaptic neuron activates many AMPA-type channels, causing strong depolarization in postsynaptic neuron
4) **Mg2+ ions are expelled from the NMDA channels **bc of this depolarization b/c their attraction from the inside of the membrane is reduced
5) **Ca2+ flows **into **postsynaptic neuron **through **NMDA channels; **activates enzymes; produces long-lasting changes in pre-postsynaptic neuron communication which underlies formation of memories
