Module 2 Lecture 5 Flashcards
how is diversity of GluAs increased
through post-transcriptional mechanisms
what kind of modifications do AMPA receptors undergo
post-transcriptional, pre-translational
- nRNA editing
- alternative splicing
what does alternative splicing affect in AMPA subunits
rate of desensitization
- controls whether flip or flop is expressed
do flops or flips tend to desensitize faster
flops
what does mRNA editing alter
Ca2+ permeability
what happens if glutamine is changed to an arginine in GluA2 subunits
gets rid of Ca2+ permeability (goes from nonpolar to a positive residue)
- nearly 100% of GluA2 subunits have undergone this editing & are impermeable to Ca2+
what are the differences in postsynaptic currents produced by
AMPA and NMDA receptors
- AMPA receptor EPSCs are fast and large
- NMDA receptor EPSCs are slower and smaller
NMDAR structure
similar to AMPAR
- additional binding sites for co-agonist glycine and an extracellular Ca2+ binding site/pocket
what determines how long the NMDAR channel stays open
subunit composition
what subunit is required for form a functional NMDAR
GluN1
- other subunits affect the kinetics of gating
what subunit composition of NMDAR is expressed early in development
NR1a/NR2D
what subunit composition of NMDAR is expressed in adulthood
NR1a/NR2A
what ions do NMDAR conduct
Na+, K+, and Ca2+
what does NMDAR require to open
glutamate and co-agonist glycine (glycine usually present)
what is NMDAR blocked by, and when
by Mg2+ ions at hyperpolarized potentials (if they open at negative membrane potential), and at rest
what does excessive NMDAR activity cause
brain damage during stroke
implications of NMDAR activity
synaptic plasticity, learning & memory
NMDAR antagonist
ketamine
what two conditions are required for NMDAR to open
- bind glutamate
- intracellular depolarization (such as from another input causing depolarization/action potentials)
when does Mg2+ pop off NMDAR
when voltage inside the cell increases
what happens if glutamate is released onto a weak synapse with an NMDAR
the glutamate binds to both AMPA and NMDA receptors, but only the AMPA receptors pass current, bc the NMDA receptors are blocked by Mg2+
- Na+ entry through AMPA receptors generates some depolarization, but not enough to trigger an AP< and not enough to unblock Mg2+ from the NMDAR
role of presynaptic axon in AMPAR and NMDAR
stimulation causes pre-synaptic AP, trigger glutamate release from terminal
what happens if glutamate is released onto a weak synapse with an NMDA receptor but there is a coincident strong input elsewhere
evoked depolarization of the neuron by the stronger synapse kicks the magnesium block off the NMDA receptor at the weak synapse, at the same time that the NMDA receptor is binding glutamate
- the NMDA receptor can now pass current, and it allows Ca2+ to enter the neuron
are NMDA receptors and AMPA receptors at the same or different synapses?
some synapses only have AMPA, some have both AMPA and NMDA, some only have NMDA (silent synapses)
what is a silent synapse
can receive signals, but they can’t convert them into current
- putting AMPA receptors on them = not silent anymore
how is the Mg2+ block released
depolarization of the postsynaptic neuron by activation of AMPA receptors at the same time and neighboring synapses
what does activation of NMDARs cause
Ca2+ influx
what does Ca2+ do in metabotropic signaling
activates intracellular signaling pathways
types of second messengers
Ca2+, cyclic AMP, cyclic GMP, IP3, diacylglycerol
sources of Ca2+
plasma membrane, endoplasmic reticulum
sources of Ca2+ in the plasma membrane
- voltage-gated Ca2+ channels
- various ligand-gated channelss
sources of Ca2+ in the endoplasmic reticulum
- IP3 receptors
- ryanodine receptors
intracellular targets for Ca2+
calmodulin, protein kinases, protein phosphates, ion channels, synaptotagmins, many other Ca2+ binding proteins
Ca2+ removal mechanisms in the plasma membrane
Na+/Ca2+ exchanger, Ca2+ pump
Ca2+ removal mechanisms in the endoplasmic reticulum
Ca2+ pump
cyclic AMP source
adenylyl cyclase acts on ATP
cyclic AMP intracellular targets
protein kinase A, cyclic nucleotide-gated channels
cyclic AMP removal mechanisms
cAMP phosphodiesterase
cyclic GMP sources
guanylyl cyclase acts on GTP
cyclic GMP intracellular targets
protein kinase G, cyclic nucleotide-gated channels
cys-loop receptors
nAChR, GABAA, glycine, and 5-HT3
- usually heteropentameric
M2 p-loop receptors
AMPAR and NMDAR
- usually heterotetrameric
what superfamily do most GPCRs belong to
hepptahelical superfamily
characteristics of GPCR subtypes/subunits
- 7 TM alpha helical regions - very highly conserved across related subtypes
- mostly exist as monomers (some can be found as homo or heterodimers; mGluR always a dimer, GABAB always a heterodimer with one of each subtype)
subunits of GABAB
heterodimer: one GABAB1 subunit and one GABAB2 subunit
what happens when GPCR is bound by the appropriate ligand
the cytosolic surface undergoes a conformational change, usually due to movement of the sixth TM region further to the inner side of the membrane
- allows G proteins to bined
what do mGluR and GABAB dimers have that’s similar to the ionotropic GluR clamshell
a venus flytrap domain at their N-terminals
what does binding of 2 glutamate or 1 GABA to the GABAB1 subunit flytrap cause
a conformational shift and G-protein binding
heterotrimeric G-protein subunits
alpha, beta, gamma
characteristics of G-protein alpha subunits
can bind GDP or GTP
what does GDP binding lead to in a GPCR
binding to beta and gamma to form a trimer/G-protein
what happens when GPCRs bind their ligand
g-proteins bind, allowing GTP to replace GDP
what happens when GTP replaced GDP
dissociation and allows the activated alpha or beta-gamma subunits to affect effector proteins and other molecules
GTPase-activating protein function (GAPs)
inactivate G-proteins
what is the function of the amplification of signalizing cascades
allow GPCRs to produce long-lasting and varied effects
transmitter role in GPCR
binds to receptor
receptor role in GPCR
activated G protein
G protein role in GPCR
alters activity of effector molecule
effector molecule role in GPCR
changes concentration of second messenger
second messenger role in GPCR
modulates activity of enzyme, and modulates activity of target
- affect the rates at which kinases and phosphatases phosphorylate proteins
enzyme role in GPCR
modulates activity of target
what does upregulation of CREB do
crucial for many cellular processes, including memory formation
