L7 Chemistry and Physiology of the Synapse Flashcards
what does PSP stand for
-PSPs: post-synaptic potentials
what are the 2 different families of Postsynaptic receptors
1)ligand-gated ion channels
(Ionotropic Rs, fast transmission)
2) G-protein-coupled-receptors
(Metabotropic Rs)
(look at slide 7)
what type of transmissions are done by ionotropic receptors
-Ligand gated ion channels are responsible for fast transmission of information to the postsynaptic neuron
please state what these terms mean:
pharmacology
agonist
antagonist
kinetics
selectivity
conductance
pharmacology – what transmitter binds to the receptor and how drugs interact with them
agonist - a drug that can combine with a receptor on a cell to produce a physiological reaction antagonist – a drug that blocks the activity of the agonist or endogenous ligand (neurotransmitter)
kinetics - rate of transmitter binding and channel gating determine the duration of their effects
selectivity – what ions are fluxed (Na+, Cl-, K+ and/or Ca2+)
conductance – the rate of flux helps determine effect magnitude
give some examples of the neurotransmitters that enable fast synaptic transmission
- Glutamate ionotropic receptors in general flux Na+, which causes an EPSP (Excitatory Post Synaptic Potential) 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.
GABA ionotropic receptors flux Cl-, which causes an IPSP (Inhibitory Post Synaptic Potential) hyperpolarizing the postsynaptic neuron. This inhibits the neuron from firing unless there is sufficient glutamate stimulation to counteract the hyperpolarization.
Acetylcholine, serotonin and ATP also activate ionotropic receptors.Nicotinic receptors at the neuromuscular junction are the most well studied ionotropic receptors. Their activation by acetylcholine causes the excitation and contraction of muscle cells.An integration of all the changes in membrane potential will decide whether a postsynaptic neuron will fire an action potential or not.
what ions go through during an EPSP Excitatory Postsynaptic Potential
(sodium & calcium in, potassium out)
what ion goes in during a IPSP Inhibitory Postsynaptic Potential
- chloride ions
what can occur during synaptic integration
signals that are EPSP Excitatory Postsynaptic Potential
IPSP Inhibitory Postsynaptic Potential:
Giving both inhibitory and excitatory signals t the same dendrite/axon
(slide 17)
what are the 3 types of ionotropic receptors that respond to glutamate
1) NMDA
2) AMPA
3) Kainate
describe the pharmacology (agonists and antagonists of the ionotropic GLuRs )
1) NMDA receptors Agonist NMDA (N-methyl D-aspartate) Antagonist APV (2-amino-5-phosphonovaleric acid)
2) AMPA receptors Agonist AMPA (a-amino-3-hydroxy-5-methylisoxazole-4-propionic acid) Antagonist CNQX (6-cyano-7-nitroquinoxaline-2,3-dione)
3) Kainate receptors
Agonist Kainic acid
Antagonist CNQX (6-cyano-7-nitroquinoxaline-2,3-dione)
describe the selectivity and conductance of AMPA and Kainate receptors
-Fast opening channels permeable to Na+ and K+
Responsible for early phase EPSP
describe- e the selectivity and conductance of GLuRs
1)Slow opening channel – permeable to Ca2+ as well as Na+ and K+
BUT also
2) requires an extracellular glycine as a cofactor to open the channel
3) 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.
—NMDA receptors responsible for a late phase EPSP
—Activated only in an already depolarized membrane in the presence of glutamate
describe the regulation of NMDA channels
EPSPs measured from resting potential higher than Mg2+ blockade. In presence or absence of AMPA or NMDA antagonists. Slower kinetics of NMDA channel -late phase EPSP
Influx of Ca2+ as well as Na+ leads to activation of a number of enzymes and other cellular events that cause widespread changes in the postsynaptic cell (neuroplasticity). This action of NMDA receptors and the resultant neuroplasticity may be the molecular mechanisms that leads to long term memory formation.
describe the 2 outcomes that occur as a result of dysregulation of NMDA receptors
1)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
2)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).
name some other inotropic receptors and whether their excitatory r inhibitory
- Glutamate - excitatory
GABA(A) - inhibitory (brain)
Glycine - inhibitory (spinal cord and brain stem)
Nicotine - excitatory at NMJ (neuromuscular junction)
- excitatory or modulatory in the CNS
Serotonin -excitatory or modulatory
ATP - excitatory
(GABA, serotonin and nicotinic receptors in lecture L13)
describe metabotropic receptors
- They transduce signals into the cell not directly through an ion channel but through activation of a G-protein which in turn triggers a series of intracellular events (that can lead to ion channel opening)
G-protein coupled receptors (GPCRs)
seven transmembrane domain protein
multiple receptors have been
described for every known
neurotransmitter
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
describe the pathways of the secondary messenger systems Gs,q & I.
Gs: when stimulated by norepinephrine
Increases:
- causes activation of adenylyl cyclase
- produce cAMP
- activates PKA
- increases protein phosphorylation
2) Gq: (activated by glutamate) - activates phospholipase C
- can either activate IP3/diacylglycerol—Ca 2+ release/PKC
- both lead to increase in protein phosphorylation and activates calcium-binding protein
3) Gi: Decreases
adenylyl cyclase
cAMP
PKA
therefore decrease in protein phosphorylation
describe the activation of G-Protein related channels
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) a subunits have intrinsic GTP-GDP enzymatic activity allowing the signal to be transient: the break down from GTP to GDP switches off its activity
6) at this point the heteromer recomplexes and awaits activation by ligand binding to another receptor.
describe which structures of the G-protein activates which enzyme of which pathway
a subunits (~20)
Gs stimulates adenylyl cyclase
Gi inhibits adenylyl cyclase
Gq stimulates phospholipase C
what occurs if the beta complexes of the G-protein are activated
- bg complexes (5 b and 12 g)
Activate K+ channels directly (G-protein gated ion channel). This is the mode of action for muscarinic ACh receptors in the heart and the GABA(B)receptor.
(Relatively fast acting and local effect, “shortcut pathway”)
describe the shortcut pathway
- receptor- G-protein- channel
- caused by the splitting of the Alpha and gamma-beta part, where gamma-beta activates the channel
-It does not involve other chemical intermediaries.
e.g. muscarinic receptors in the heart, GABA(B) Receptors.
Responses within 30-100 msec of NT binding. Localised responses.
slide 28
what subunit activates the secondary messengers
- Alpha
describe in short the Gq pathway
-Gq activates phospholipase C (PLC) which converts PIP2 into IP3 and diacylglycerol (DAG).
DAG activates protein kinase C (PKC) and IP3 releases Ca2+ from internal stores which activates Ca2+-dependent enzymes.
what are kinases and phosphatases regulated by
- variety f secondary messengers
what is a long-term synaptic change
structural and biochemical
recruitment of new receptors
(LTP/synaptic plasticity.)
how can G-protein signals be amplified
- G-protein signalling provides a
method of amplifying signals between neuronsone 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
describe how presynaptic receptors are modulated
- Presynaptic receptors - change amount of transmitter releasedautoreceptors regulate release of transmitter by modulating its synthesis, storage, release or reuptake
e.g. phosphorylation of tyrosine hydroxylaseheteroreceptors (axoaxonic synapses or extrasynaptic)
regulate synthesis and/or release of transmitters other than their own ligand
e.g. NE can influence the release of ACh by modulating α-adrenergic receptors
describe how postsynaptic receptors are modulated by activation
- Postsynaptic receptors - change firing pattern or activityincrease 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 3 types of metabotropic glutamate receptors
Group I: mGluR1+5Gq
Group II: mGluR2+3 Gi Group III: mGluR4,6,7+8 Gi
give more examples of metabotropic receptors in the body
GABA(B) receptor
muscarinic acetylcholine receptors
dopamine receptors
noradrenergic and adrenergic receptors
serotonin receptors
neuropeptide receptors
what are the 2 other types of receptors not discussed that much in this lecture
1)Enzyme-linked receptors
e.g. Receptor tyrosine kinases
Transmembrane proteins with intrinsic tyrosine kinase activity activated by neurotrophin binding (e.g. NGF, BDNF)
On activation autophosphorylate
phosphorylate intracellular regulatory subunits
signal transduction cascades
2) Membrane permeant signaling molecules activate intracellular receptors.
