Chemistry and physiology of the synapse L7 Flashcards
What are ionotropic receptors
Ligand gated ion channels are responsible for fast transmission of info to the postsynaptic neuron
How are ionotropic receptors activated
Opened by ligand binding rather than voltage changes(ligand = neurotransmitter)
It binds to the channel, changes its conformation, thus opening it and allowing ions to flux through central pore
How many subunits form the channels that form the central pore
4 or 5 subunits
How do glutamate ionotropic receptors function
Glutamate iontropic receptors in general flux Na+, which causes an EPSP depolarizing the postsynaptic neuron
Enough depolarization, due to multiple receptors being activated or repeated activation, can cause the postsynaptic cell to fire an action potential
How do GABA ionotropic receptors function?
GABA ionotropic receptors flux Cl-, which causes an IPSP hyperpolarizing the postsynaptic neuron
This inhibits the neuron from firing unless there is sufficient glutamate stimulation to counteract the hyperpolarization
What other chemicals also activate GABA ionotropic receptors?
Ach, serotonin and ATP
What is synaptic integration?
Combination of all the changes in membrane potential will determine whether a postsynaptic neuron will fire an action potential or not
What are the three types of ionotropic receptors that respond to glutamate
1) NDMA
2) AMPA
3) Kainate
Agonist and antagonist for NDMA receptors
Agonist - NDMA(N-methyl D-aspartate)
Antagonist - APV(2-amino-5-phosphonovaleric acid)
Agonist and antagonist for AMPA receptors
Agonist - AMPA
Antagonist - CNQX
Agonist and antagonist for kainate receptors
Agonist - Kainic acid
Antagonist - CNQX
Describe non-NDMA glutamate receptors
- Fast opening channels permeable to Na+ and k+
- Responsible for early phase EPSP
Describe NMDA receptors
- Slow opening channel - permeable to Ca2+ as well as Na+ and K+
- Requires an extracellular glycine as a cofactor to open the channel
- It is also gated by membrane voltage - Mg2+ ion plugs pore at resting membrane potentials
- When membrane depolarizes Mg2+ ejected from channel by electrostatic repulsion allowing conductance of the other cations, activity-dependent synaptic modification
What potentials are NMDA receptors responsible for
Late phase EPSP
When are NMDA receptors activated
Activated only in an already depolarized membrane in the presence of glutamate
What does the influx of Ca2+ as well as Na+ through NMDA receptors lead to
Activation of a number of enzymes and other cellular events that cause widespread changes in the postsynaptic cell(neuroplasticity)
The activation of NMDA receptors and the resultant neuroplasticity may be the molecular mechanisms that lead to long term memory formation
Link between NMDA receptors and schizophrenia
- NMDA receptors also inhibited by phencyclidine(PCP angel dust) and MK801; both bind in the open pore
- Blockade of NMDA receptors in this way produces symptoms that resemble the hallucinations associated with schizophrenia
- Certain antipsychotic drugs enhance current flow through NMDA channels
What is glutamate excitotoxicity
- Excessive Ca2+ influx into the cell, which activates calcium-dependent enzymes that degrade proteins, lipids and nucleic acids
- This kind of cell damage occurs after cardiac arrest, stroke, oxygen deficiency, and repeated intense seizures(status epilepticus)
What are some other ionotropic receptors besides GABA and Glutamate
Glycine - Inhibitory(spinal cord and brain stem)
Nicotine - Excitatory at NMJ, excitatory and modulatory in the CNS
Serotonin - excitatory or modulatory
ATP - excitatory
How do metabotropic receptors function
- Transmitter binds to extracellular domain of receptor
- Binding triggers uncoupling of a heteromeric g-protein on the intracellular surface
- Transduces signal across the cell membrane
What are Gs, Gq and Gi
Three different types of heterotrimeric(made of 3 different parts) proteins
Path for norephinephrine stimulation
Norephinephrine –> beta-adrenergic receptor –> Gs –> cAMP –> Protein kinase A –> increase protein phosphorylation
Path for glutamate stimulation(dg pathway)
Glutamate –> mGluR –> Gq –>activates Phospholipase C(PLC) –> converts PIP2 into IP3 and Diacylglycerol –> Protein kinase c –> Increase protein phosphorylation and activate calcium-binding proteins
Path for glutamate stimulation(ip3 pathway)
Glutamate –> mGluR –> Gq –> activates Phospholipase c –> converts PIP2 into IP3 and diacylgylcerol(DAG), IP3 –> Ca2+ release –> increase protein phosphorylation and activate calcium-binding proteins
path for dopamine stimulation
Dopamine –> Dopamine D2 receptor –> Gi –> - adenylyl cyclase –> - cAMP –> - protein kinase A –> decrease protein phosphorylation
Describe how G-protein coupled receptors work
1) In resting state, the heteromer is bound to GDP
2) On binding of a ligand to the receptor, the GDP is switched for a GTP and the heteromer splits in two
3) The Ga subunit and Gbg complex divide and diffuse separately through the membrane
4) These individual entities are able to stimulate activity of other effector proteins
5) Alpha subunits have intrinsic GTP-GDP enzymatic activity allowing the signal to be transient: the breakdown from GTP to GDP switches off its activity
6) At this point, the heteromer recomplexes and awaits activation by ligand binding to another receptor
What is the shortcut pathway for g-protein receptors
Receptor –> G-protein –> ion channel
It does not involve other chemical intermediaries. eg muscarinic receptors in the heart, GABA(B) receptors
Responses within 30-100msec of nt binding. Localised responses
How does G-protein signalling amplify signals
- G-protein signalling provides a method of amplifying signals between neurons
- One transmitter bound receptor can uncouple multiple g-protein heteromers
- The signal can be amplified at every stage
- What begins as a weak signal at the synapse can cause an amplified response in the postsynaptic cell
What are the types of presynaptic receptors that modulate signals
Presynaptic receptors - change amount of transmitter released
Autoreceptors and heteroreceptors
How do autoreceptors modulate signals
Regulate release of transmitter by modulating its synthesis, storage, release or reuptake
eg phosphorylation of tyrosine hydroxylase
How do heteroreceptors modulate signals
Heteroreceptors(axoaxonic synapses or extrasynaptic) regulate synthesis and/or release of transmitter other than their own ligand
eg NE can influence the release of ACh by modulating alpha adrenergic receptors
How do postsynaptic receptors modulate signals
- Change firing pattern or activity
- Increase or decrease rate of cell firing(directly by action at ligand gated ion channels or indirectly G-protein or phosphorylation-coupled channels
- Long term synaptic changes
What are the classifications of metabotropic receptors
- Group 1 - mGluR1+5 Gq
- group II - mGluR2+3 Gi
- Group III - mGluR4,6,7+8 Gi
GABA(B) receptor
Muscarinic acetylcholine receptors
Dopamine receptors
Noradrenergic and adrenergic receptors
Serotonin receptors
Neuropeptide receptors
How do enzyme-linked receptors work
1) Enzyme-linked receptors eg(receptor tyrosine kinases)
- Transmembrane protein with intrinsic tyrosine kinase activity activated by neurotrophin binding(eg NGF, BDNF)
- On activation autophosphoryl
phosphorylate intracellular regulatory subunits - Signal transduction cascades
How do membrane permanent signalling molecules work?
- Activate intracellular receptors
