Chemistry and physiology of the synapse L7

Question 1

What are ionotropic receptors

Answer 1

Ligand gated ion channels are responsible for fast transmission of info to the postsynaptic neuron

Question 2

How are ionotropic receptors activated

Answer 2

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

Question 3

How many subunits form the channels that form the central pore

Answer 3

4 or 5 subunits

Question 4

How do glutamate ionotropic receptors function

Answer 4

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

Question 5

How do GABA ionotropic receptors function?

Answer 5

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

Question 6

What other chemicals also activate GABA ionotropic receptors?

Answer 6

Ach, serotonin and ATP

Question 7

What is synaptic integration?

Answer 7

Combination of all the changes in membrane potential will determine whether a postsynaptic neuron will fire an action potential or not

Question 8

What are the three types of ionotropic receptors that respond to glutamate

Answer 8

1) NDMA
2) AMPA
3) Kainate

Question 9

Agonist and antagonist for NDMA receptors

Answer 9

Agonist - NDMA(N-methyl D-aspartate)

Antagonist - APV(2-amino-5-phosphonovaleric acid)

Question 10

Agonist and antagonist for AMPA receptors

Answer 10

Agonist - AMPA

Antagonist - CNQX

Question 11

Agonist and antagonist for kainate receptors

Answer 11

Agonist - Kainic acid

Antagonist - CNQX

Question 12

Describe non-NDMA glutamate receptors

Answer 12

• Fast opening channels permeable to Na+ and k+

- Responsible for early phase EPSP

Question 13

Describe NMDA receptors

Answer 13

• 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

Question 14

What potentials are NMDA receptors responsible for

Answer 14

Late phase EPSP

Question 15

When are NMDA receptors activated

Answer 15

Activated only in an already depolarized membrane in the presence of glutamate

Question 16

What does the influx of Ca2+ as well as Na+ through NMDA receptors lead to

Answer 16

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

Question 17

Link between NMDA receptors and schizophrenia

Answer 17

• 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

Question 18

What is glutamate excitotoxicity

Answer 18

• 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)

Question 19

What are some other ionotropic receptors besides GABA and Glutamate

Answer 19

Glycine - Inhibitory(spinal cord and brain stem)

Nicotine - Excitatory at NMJ, excitatory and modulatory in the CNS

Serotonin - excitatory or modulatory

ATP - excitatory

Question 20

How do metabotropic receptors function

Answer 20

• 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

Question 21

What are Gs, Gq and Gi

Answer 21

Three different types of heterotrimeric(made of 3 different parts) proteins

Question 22

Path for norephinephrine stimulation

Answer 22

Norephinephrine –> beta-adrenergic receptor –> Gs –> cAMP –> Protein kinase A –> increase protein phosphorylation

Question 23

Path for glutamate stimulation(dg pathway)

Answer 23

Glutamate –> mGluR –> Gq –>activates Phospholipase C(PLC) –> converts PIP2 into IP3 and Diacylglycerol –> Protein kinase c –> Increase protein phosphorylation and activate calcium-binding proteins

Question 24

Path for glutamate stimulation(ip3 pathway)

Answer 24

Glutamate –> mGluR –> Gq –> activates Phospholipase c –> converts PIP2 into IP3 and diacylgylcerol(DAG), IP3 –> Ca2+ release –> increase protein phosphorylation and activate calcium-binding proteins

Question 25

path for dopamine stimulation

Answer 25

Dopamine –> Dopamine D2 receptor –> Gi –> - adenylyl cyclase –> - cAMP –> - protein kinase A –> decrease protein phosphorylation

Question 26

Describe how G-protein coupled receptors work

Answer 26

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

Question 27

What is the shortcut pathway for g-protein receptors

Answer 27

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

Question 28

How does G-protein signalling amplify signals

Answer 28

• 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

Question 29

What are the types of presynaptic receptors that modulate signals

Answer 29

Presynaptic receptors - change amount of transmitter released

Autoreceptors and heteroreceptors

Question 30

How do autoreceptors modulate signals

Answer 30

Regulate release of transmitter by modulating its synthesis, storage, release or reuptake

eg phosphorylation of tyrosine hydroxylase

Question 31

How do heteroreceptors modulate signals

Answer 31

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

Question 32

How do postsynaptic receptors modulate signals

Answer 32

• 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

Question 33

What are the classifications of metabotropic receptors

Answer 33

• 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

Question 34

How do enzyme-linked receptors work

Answer 34

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

Question 35

How do membrane permanent signalling molecules work?

Answer 35

• Activate intracellular receptors