T1 L7 Chemistry & physiology of the synapse Flashcards
What are the 4 main types of transmitters?
Amino acids
Monoamines
Acetylcholine
Neuropeptides
What is a ligand?
Neurotransmitter
Binds to the channel, changing its conformation to open it & allow ions to flux through the central pore
What is the definition of pharmacology?
What transmitter binds to the receptor & how drugs interact with them
What is an agonist?
A drug that can combine with a receptor on a cell to produce a physiological reaction
What is an antagonist?
A drug that blocks the activity of the agonist or endogenous ligand
What is the definition of kinetics?
Rate of transmitter binding & channel gating determine the duration of their effects
What is the definition of selectivity?
What ions are fluxed
What is the definition of conductance?
The rate of flux helps determine effect magnitude
What do glutamate ionotropic receptors do?
Flux Na+
Causes an EPSP depolarising the postsynaptic neuron
What do GABA ionotropic receptors do?
Flux Cl-
Causes an IPSP hyper polarising the postsynaptic neuron
Inhibits the neuron from firing unless there is sufficient glutamate stimulation to counteract the hyperpolarisation
What else can activate ionotropic receptors?
Acetylcholine
Serotonin
ATP
What activates nicotinic receptors?
Acetylcholine
What happens when nicotinic receptors are activated?
Excitation & contraction of muscle cells
What 3 types of ionotropic receptors respond to glutamate?
NMDA
AMPA
Kainate
What is the agonist & antagonist for NMDA receptors
Agonist - NMDA
Antagonist - APV
What is the agonist & antagonist for AMPA receptors?
Agonist- AMPA
Antagonist - CNQX
What is the agonist & antagonist for kainate receptors?
Agonist - kainic acid
Antagonist - CNQX
What is APV?
An antagonist to NMDA receptors
Describe non-NMDA receptors
Fast opening channels permeable to Na+ & K+
Responsible for early phase EPSP
Describe the NMDA receptor
Slow opening channel
Requires extracellular glycine as a cofactor to open the channel
Gated by membrane voltage
Describe the gating of the NMDA receptor
Mg2+ plugs pore at resting membrane potential
When membrane depolarises, Mg2+ is ejected from the channel by electrostatic repulsion allowing conductance of other cations, activity-dependent synaptic modification
Describe the link between NMDA receptors & schizophrenia
NMDA receptors are inhibited by phencyclidine & MK801
Blockade of NMDA receptors in this way produces symptoms that resemble hallucinations associated with Schizophrenia
Describe glutamate excitotoxicity
Excessive calcium influx into the cell activates calcium-dependent enzymes that degrade proteins, lipids & nucleic acids
When does glutamate excitotoxicity cell damage occur?
After a cardiac arrest
Stroke
Oxygen deficiency
Repeated intense seizures
What are some other examples of ionotropic receptors?
Glutamate - excitatory
GABA(A) - inhibitory (brain)
Glycine - inhibitory (spinal cord & brain stem)
Nicotine - excitatory at NMJ. Excitatory or modulatory in CNS
Serotonin - excitatory or modulatory
ATP - excitatory
How do metabotropic receptors work?
Transduce signals into the cell through activation of a G-protein which triggers a series of intracellular evens
Describe G-protein coupled receptors
7 transmembrane domain protein
Transmitter binds to extracellular domain & triggers uncoupling of a heteromeric G-protein on intracellular surface
Transduce signal across cell membrane
Give the steps of G-proteins
1) In resting state the heteromer is bound to GDP
2) on binding of a ligand to the receptor the GDP is switched to GTP & heteromer splits in 2
3) Ga subunit & Gby complex divide & diffuse separately through membrane
4) individual parts are able to stimulate activity of other effector proteins
5) a subunits have intrinsic GTP-GDP enzymatic activity allowing the signal to be transient. The breakdown from GTP to GDP switches off its activity
6) Heteromer recomplexes & awaits activation by ligand binding to another receptor
Describe the alpha subunit system
Gs stimulates adenylyl cyclase
Gi inhibits adenylyl cyclase
Gq stimulates phospholipase C
Describe the By complex system
Activate K+ channels directly
Mode of action for muscarinic acetylcholine receptors in heart & GABA(B) receptor
Give the steps of the PIP2 second messenger cascade
1) Gq activates phospholipase C
2) Converts PIP2 into IP3 & DAG
3) DAG activates PKC
IP3 releases Ca2+ from internal stores which activates Ca2+ dependent enzymes
What does protein kinase do?
Phosphorylates a protein
What is the purpose of amplification of G-protein signalling?
Provides a method of amplifying signals between neurons
How are G-protein signals amplified
1 transmitter bound receptor can uncouple multiple G-protein heteromers
Signal can be amplified at every stage
A weak signal at the synapse can cause an amplified response in the postsynaptic cell
What effect do autoreceptors have on presynaptic receptors?
Regulate release of transmitter by modulating its synthesis, storage, release or reuptake
What effect do heteroceptors have on presynaptic receptors?
Regulate synthase and/or release of transmitter
How can NE influence the release of ACh?
By modulating alpha-adrenergic receptors
Give examples of metabotropic receptors
Metabotropic glutamate receptors GABA(B) receptors Muscarinic acetylcholine receptors Dopamine receptors Noradrenergic & adrenergic receptors Serotonin receptors Neuropeptide receptors
What are receptor tyrosine kinases?
Transmembrane proteins with intrinsic tyrosine kinase activity activated by neurotrophin binding
What happens on activation of receptor tyrosine kinases?
On activation they autophosphorylate
Phosphorylate intracellular regulatory subunits
Signal transduction cascades
