Lecture 10. Glutamatergic Synaptic Transmission and the Trafficking of Transmembrane Receptors Flashcards
What is the major excitatory neurotransmitter in the mammalian CNS?
L-Glutamate
What are L-glutamate ligand-gated ion channels called?
Ionotropic GluRs (iGluR)
What are L-glutamate G-protein coupled receptors called?
Metabotropic GluRs (mGluR)
What are the three types of iGluRs?
NMDA receptor
AMPA receptor
Kainate receptor
What G-protein are coupled to group I mGluRs?
Gαq
What G-protein are coupled to group II mGluRs?
Gαi
What G-protein are coupled to group III mGluRs?
Gαi
What is the obligatory receptor of NMDA?
GluN1 (has to be there or else not a NMDA receptor)
What are the three subunits of NMDA receptors?
GluN1
GluN2A-D
GluN3A,B
What are the four subunits of AMPA receptors?
GluA1-4
What are the five subunits of kainate receptors?
GluK1-5
What are the two subtypes of mGluR group I?
mGlu1
mGlu5
What are the two subtypes of mGluR group II?
mGlu2
mGlu3
What are the four subtypes of mGluR group III?
mGlu4
mGlu6
mGlu7
mGlu8
What effect are brought about by iGluRs?
Fast, excitatory
What effect are brought about by mGluRs?
Slow, excitatory or inhibitory
How does glutamate arise in the synapse?
Either converted from glutamine taken up by the neurone from a glial cell/astrocyte or as a product of the tricarboxylic acid cycle
How is glutamate packed into vesicles?
Through the creation of a H⁺ ion gradient that supports the uptake of Glu⁻
What uptakes glutamate, allowing glutamate supply to be recycled?
EAAT1-4 (excitatory amino acid transporter)
What EAATs are located on the glial cell?
EAAT1-2
What EAATs are located on the neurone?
EAAT3-4
Why do glial cells possess EAAT?
Due to being in close proximity of the neurone (tripartite synapse)
How many agonists must bind to the NMDA receptor to activate it?
2
What ion blocks the transmembrane pore?
Mg²⁺
What are the co-agonists of the NMDA receptor that bind to GluN1?
Glycine and D-serine (normally always present so don’t think about them)
What ion regulatory site is present on GluN2?
Zn²⁺
What does rectifying mean?
When the flow of ions through a channel is favoured in one direction supposed to the other direction
What can AMPA receptor subunits affect?
Function, can fine tune activity due to certain stimuli. Can cause post-translational modifications that can influence the function of particular circuits
What does arginine block?
Ca²⁺
What is the difference in I/V curve between Ca²⁺-permeable and Ca²⁺-impermeable AMPA receptors?
Ca²⁺-permeable = rectifying
Ca²⁺ impermeable = linear
What are the roles of glutamate receptors in the mammalian brain?
Mediate the majority of fast excitatory synaptic transmission in the CNS
Vital to many basic functions – cognition, movement, central cardiovascular, thermoregulatory & respiratory control
Changes in glutamatergic synaptic strength may underpin learning and memory
Implicated in a host of neurodevelopmental, neurological, neurodegenerative and psychiatric conditions (eg autism, epilepsy, stroke, Alzheimer’s disease, schizophrenia)
Target of drugs of abuse – Ketamine (Special K), Phencyclidine (PCP; Angel Dust)
What are the trafficking levels into and out of synapses?
Very high
Why does Mg²⁺ block NMDA receptors when the cell is hyperpolarised?
The ion is more strongly attracted to the receptor, ion attracted more strongly into the channel
What are active synapses?
Transmits information at hyperpolarised (resting) membrane potentials through AMPA receptors
What are silent synapses?
Ones that lacks AMPARs at the synapse and does NOT transmit information at hyperpolarised (resting) membrane potentials due to the Mg²⁺ block of the NMDA receptor. AMPA receptors may be stored in intracellular vesicles or at extrasynaptic sites
Synapses containing NMDAR can recruit what?
AMPAR through pairing protocol (creates response at -65mV)
How can the movement of AMPARS to the synaptic cleft be visualised?
Through the use of a latex bead or staining with a quantum dot
What is long-term potentiation?
When high plasticity is induced in the brain thorough high frequency stimulation
What is long-term depression?
When low plasticity is induced in the brain thorough low frequency stimulation, decreasing the size of the response
What are NMDARs necessary for?
Long-term potentiation and spatial learning
What are the implications of AMPAR trafficking at synapses?
Trafficking may underlie learning and memory, as well as a host of pathological and psychiatric conditions
This clinical relevance encourages the synthesis of subtype/subunit selective GluR-based drugs and hopes for new treatments
