Ionotropic Receptors Flashcards

What are the two main types of neurotransmitter receptors?

Ionotropic (ligand-gated ion channels) and Metabotropic (GPCRs)

What are the characteristics of ionotropic receptors?

Rapid action, short-term effect, signaling

What are the characteristics of metabotropic (GPCR) receptors?

Slow onset, longer effect, modulatory

What are the three essential elements that define all ionotropic receptors?

1) Binding site for neurotransmitter, 2) Pore that spans the plasma membrane, 3) Gate that opens in response to neurotransmitter binding

What is the affinity range of ionotropic receptor binding sites?

Extremely high - often in the micromolar range and sometimes nanomolar range

How is the pore of an ionotropic receptor formed?

By subunits coming together so hydrophobic amino acids point toward lipid bilayer while hydrophilic amino acids line the pore

What is another name for ionotropic neurotransmitter receptors?

Ligand-gated ion channels

What determines the effect of neurotransmitter binding to an ionotropic receptor?

The ion(s) that flow through the channel from one side of the membrane to the other

What happens when a non-specific cation channel opens?

Drives depolarization as inward flow of Na+ dominates the response

What happens when a ligand-gated Cl- channel opens?

Produces hyperpolarization because inward flow of Cl- is an outward flow of current

What are the two structural types of synapses?

Type I (asymmetric) and Type II (symmetric)

What characterizes a Type I (asymmetric) synapse?

Substantial difference in thickness of pre- and post-synaptic membranes; extremely wide postsynaptic density (PSD)

What characterizes a Type II (symmetric) synapse?

Membrane specializations at presynaptic active zone and postsynaptic density are equal in thickness

Where are Type I (asymmetric) synapses found?

Where one neuron forms an excitatory connection with another (EPSPs occur); preferred sites on dendritic spines

Where are Type II (symmetric) synapses found?

Locations where IPSPs can be recorded - inhibitory synapses

What neurotransmitter is released at Type I synapses?

Glutamate

What neurotransmitters are released at Type II synapses?

GABA and glycine

What are ionotropic glutamate receptors?

Cation channels

What are ionotropic GABA and glycine receptors?

Cl- channels

What size gold particles were used to label glutamate in electron microscopy experiments?

10 nm (20 nm) gold particles attached to antibodies to glutamate

What size gold particles were used to label GABA in electron microscopy experiments?

25 nm (40 nm) gold particles attached to antibodies against GABAHow many subunits make up nicotinic ACh receptors, GABA receptors, glycine receptors, and 5-HT3 receptors?|Five subunits (pentamers)

How many subunits make up ionotropic glutamate receptors?

Four subunits (tetramers)

How many transmembrane helices do nicotinic ACh, GABA, glycine, and 5-HT3 receptor subunits have?

Four complete transmembrane helices

How many transmembrane domains do ionotropic glutamate receptor subunits have?

Three complete transmembrane helices (M1, M3, M4) and a pore loop (M2)

What do ionotropic glutamate receptors resemble structurally?

K+ channels and voltage-gated channels (due to the pore loop)

How many transmembrane helices do ionotropic ATP receptors (P2X) have?

Two transmembrane helices

Where is the glutamate binding site located?

In the extracellular part of the receptor - includes portion of N-terminus plus extracellular loop between M3 and M4

What are the three types of ionotropic glutamate receptors?

AMPA receptors, kainate receptors, and NMDA receptors

How were the three glutamate receptor types named?

Named for the agonist drug that binds to each at very high affinity

What does NMDA stand for?

N-methyl-D-aspartate

What does AMPA stand for?

Alpha-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid

What are AMPA and kainate receptors collectively called?

Non-NMDA receptors

Why are AMPA and kainate receptors grouped together as non-NMDA receptors?

Because they behave very differently from NMDA receptors in their ion selectivity and response kinetics

What determines which cations will flow through glutamate receptors?

The difference in subunit composition

What does M2 determine in glutamate receptors?

The selective cation permeability of the receptor (in the pore loop)

What subunits make up AMPA receptors?

GluR1-4 (also known as GluA1-A4)

What is the most common AMPA receptor composition in mature mammals?

Composed of R1 and R2 subunits

What type of current flows through AMPA receptors with R2 subunits?

Small amount of current carried exclusively by inward flow of Na+

What is special about AMPA receptors without R2 subunits?

Currents are much larger and carried by inward flow of both Na+ and Ca2+

What does the R2 subunit do to AMPA receptors?

Restricts flow of ions to Na+; presents a barrier to flow of Ca2+

Where are GluR2-free receptors most commonly found?

At glutamate synapses on GABA neurons of the cerebral cortex

What is the Q/R site?

A site in the pore loop of the R2 subunit where a single amino acid determines Ca2+ permeability

What does Q stand for in the Q/R site?

Glutamine

What does R stand for in the Q/R site?

Arginine

What amino acid is at the Q/R site if RNA is left unedited?

Glutamine (Q) - coded by CAG codon

What amino acid is at the Q/R site after RNA editing?

Arginine (R) - coded by CIG (behaves like CGG)

How does arginine at the Q/R site affect Ca2+ permeability?

Large, positively charged side group blocks flow of Ca2+ through channel while allowing monovalent cations (Na+, K+)

What is the permeability ratio of Na+ to Ca2+ in R2-containing AMPA receptors?

50 times more permeable to Na+ than to Ca2+

What is RNA editing?

Deamination of adenosine to inosine in the pre-mRNA

What does deamination of adenosine produce?

Inosine - which behaves like guanine in base pairing

What codon codes for glutamine?

CAG

What does the codon become after RNA editing?

CIG (inosine behaves like guanine)

What enzyme performs RNA editing on GluR2?

ADAR2 (adenosine deaminase acting on RNA type 2)

What happens in ADAR2 null mutant mice?

No R possible at Q/R site; AMPA-Rs have high conductance and are Ca2+ permeable; mice suffer intractable seizures during very short lives

Does RNA editing occur in kainate receptors?

Yes - same editing occurs in GluR5 and GluR6 subunits, making them Ca2+ impermeable

Does RNA editing occur in NMDA receptors?

No - so they remain permeable to Ca2+

What is the general importance of RNA editing?

Selective RNA editing permits expression of a single gene to produce two or more proteins with different properties

What blocks AMPA receptors without GluR2 subunits?

Voltage-dependent block by cytosolic polyamines

When is polyamine blockade less pronounced?

At hyperpolarized membrane potentials

When is polyamine blockade more pronounced?

At depolarized membrane potentials

What type of I-V relationship do non-GluR2-containing AMPA-Rs exhibit?

Inwardly rectifying current-voltage relationship

Can polyamine block be relieved?

Yes - can be progressively relieved by repeated activation

How can non-GluR2 AMPA-Rs regulate synaptic plasticity?

Polyamine block can be used as an activity-dependent mechanism

What are the three key features of NMDA receptors?

1) Both ligand-gated and voltage-dependent, 2) Permeable to Ca2+, 3) Require D-serine or glycine as co-agonist

What makes NMDA receptors unique among glutamate receptors?

They are voltage-dependent (simultaneously ligand-gated and voltage-dependent channels)

What must happen for NMDA receptor channels to conduct current?

Glutamate must bind AND membrane must be depolarized (usually by action potential)

What makes NMDA receptors coincidence detectors?

Channels conduct only with coincident binding of glutamate (presynaptic AP) AND depolarization of postsynaptic neuron (postsynaptic AP)

What is the key event at NMDA receptors?

Inward flow of Ca2+ as a powerful intracellular signal into cytosol beneath postsynaptic membrane

What is the primary role of NMDA receptors?

Molecular means by which strength of individual glutamate synapses can change rapidly in response to effectiveness in bringing neuron to threshold

What is the role of non-NMDA receptors (AMPA/kainate)?

Work to depolarize neurons and bring them to threshold for generating action potentials

What causes the voltage-dependence of NMDA receptors?

Binding of Mg2+ to a site in the channel pore at hyperpolarized membrane potentials

At what membrane potential does Mg2+ block NMDA receptors?

Below 0 mV (hyperpolarized range)

What happens when glutamate binds to NMDA receptor at hyperpolarized potentials?

Conformational change opens channel but Mg2+ blocks it, so no cation flows through

What relieves the Mg2+ block?

Membrane depolarization

What happens to Mg2+ at depolarized membrane potentials?

Detaches from inner surface of channel and floats into extracellular fluid (where [Mg2+] is ~1 mM)

How long does glutamate remain bound to an NMDA receptor?

20 milliseconds

What drug mimics Mg2+ action as an uncompetitive antagonist?

Memantine - clogs the receptor's ion channel

Why is Ca2+ permeability vital for NMDA receptors?

It's THE SIGNAL the postsynaptic neuron gets when presynaptic AP occurs immediately before postsynaptic AP

What concentration does intracellular Ca2+ reach around NMDA receptor pore when it opens?

Rises from 100 nanomolar to several hundred micromolar

What is the equilibrium potential for Ca2+?

+120 mV

In what direction does Ca2+ move at any membrane potential below +120 mV?

Inward

What co-agonist is required for NMDA receptors?

D-serine (or glycine)

Where is D-serine supplied from?

Astrocytes supply D-serine continuously

Why can only astrocytes produce D-serine?

Only they have the enzyme (a racemase) that converts L form to D form

What must happen for NMDA receptor channel to open?

D-serine AND glutamate must both be bound, and during the 20 ms both are bound, postsynaptic cell must generate AP

What other substances bind to NMDA receptor allosteric sites?

H+, Zn2+, phencyclidine (angel dust), ketamine (special K)

What does it mean that current flow through NMDA receptor is rectified?

It allows current to move in one direction (outward) much better than inward

At what membrane potentials does NMDA receptor show linear I-V relationship?

At 0 mV to more depolarized potentials

What happens to NMDA receptor I-V relationship at negative membrane potentials?

Inward current is tiny and shrinks as membrane becomes more hyperpolarized (due to Mg2+ block)

What happens when Mg2+ is removed from fluid bathing NMDA receptor?

Eliminates rectification; current moves equally well in both directions; becomes typical non-specific cation channel

What determines current direction through NMDA receptor without Mg2+?

Only the membrane potential

Where are NMDA receptors typically found?

Side-by-side with AMPA and kainate receptors at most glutamate synapses in CNS

What drugs selectively block different glutamate receptors?

APV (AP5) blocks NMDA receptors; CNQX blocks both AMPA and kainate receptors

At -80 mV, which glutamate receptors carry current?

Only AMPA and kainate receptors (all current blocked by CNQX; APV has no effect)

Why does APV have no effect at -80 mV?

Because Mg2+ blocks NMDA receptors at hyperpolarized membrane potentials

At -40 mV, what happens with APV and CNQX?

CNQX blocks most inward current; APV blocks small, late occurring current (few NMDA receptors have opened)

At +20 mV, what happens to current direction?

Current is now outward because membrane potential is more positive than reversal potential for cations

At +20 mV, which antagonist blocks which current component?

CNQX blocks early component; APV blocks later component (depolarization removes Mg2+ block)

What is the kinetic difference between AMPA and NMDA currents?

AMPA current is fast and brief; NMDA current is slow and prolonged

What is the reversal potential for both AMPA and NMDA receptors?

0 mV (non-specific cation channels)