L7 Chemistry and Physiology of the Synapse

Question 1

what does PSP stand for

Answer 1

-PSPs: post-synaptic potentials

Question 2

what are the 2 different families of Postsynaptic receptors

Answer 2

1)ligand-gated ion channels
(Ionotropic Rs, fast transmission)
2) G-protein-coupled-receptors
(Metabotropic Rs)

(look at slide 7)

Question 3

what type of transmissions are done by ionotropic receptors

Answer 3

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

Question 4

please state what these terms mean:

pharmacology

agonist

antagonist

kinetics

selectivity

conductance

Answer 4

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

Question 5

give some examples of the neurotransmitters that enable fast synaptic transmission

Answer 5

• 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.

Question 6

what ions go through during an EPSP Excitatory Postsynaptic Potential

Answer 6

(sodium & calcium in, potassium out)

Question 7

what ion goes in during a IPSP Inhibitory Postsynaptic Potential

Answer 7

• chloride ions

Question 8

what can occur during synaptic integration

Answer 8

signals that are EPSP Excitatory Postsynaptic Potential
IPSP Inhibitory Postsynaptic Potential:

Giving both inhibitory and excitatory signals t the same dendrite/axon

(slide 17)

Question 9

what are the 3 types of ionotropic receptors that respond to glutamate

Answer 9

1) NMDA
2) AMPA
3) Kainate

Question 10

describe the pharmacology (agonists and antagonists of the ionotropic GLuRs )

Answer 10

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)

Question 11

describe the selectivity and conductance of AMPA and Kainate receptors

Answer 11

-Fast opening channels permeable to Na+ and K+

Responsible for early phase EPSP

Question 12

describe- e the selectivity and conductance of GLuRs

Answer 12

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

Question 13

describe the regulation of NMDA channels

Answer 13

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.

Question 14

describe the 2 outcomes that occur as a result of dysregulation of NMDA receptors

Answer 14

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).

Question 15

name some other inotropic receptors and whether their excitatory r inhibitory

Answer 15

• 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)

Question 16

describe metabotropic receptors

Answer 16

• 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

Question 17

describe the pathways of the secondary messenger systems Gs,q & I.

Answer 17

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

Question 18

describe the activation of G-Protein related channels

Answer 18

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.

Question 19

describe which structures of the G-protein activates which enzyme of which pathway

Answer 19

a subunits (~20)
Gs stimulates adenylyl cyclase
Gi inhibits adenylyl cyclase
Gq stimulates phospholipase C

Question 20

what occurs if the beta complexes of the G-protein are activated

Answer 20

• 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”)

Question 21

describe the shortcut pathway

Answer 21

• 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

Question 22

what subunit activates the secondary messengers

Answer 22

• Alpha

Question 23

describe in short the Gq pathway

Answer 23

-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.

Question 24

what are kinases and phosphatases regulated by

Answer 24

• variety f secondary messengers

Question 25

what is a long-term synaptic change

Answer 25

structural and biochemical
recruitment of new receptors

(LTP/synaptic plasticity.)

Question 26

how can G-protein signals be amplified

Answer 26

• 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 27

describe how presynaptic receptors are modulated

Answer 27

• 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

Question 28

describe how postsynaptic receptors are modulated by activation

Answer 28

• 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

Question 29

what are the 3 types of metabotropic glutamate receptors

Answer 29

Group I: mGluR1+5Gq

Group II:	mGluR2+3 	Gi

Group III:	mGluR4,6,7+8	Gi

Question 30

give more examples of metabotropic receptors in the body

Answer 30

GABA(B) receptor

muscarinic acetylcholine receptors

dopamine receptors

noradrenergic and adrenergic receptors

serotonin receptors

neuropeptide receptors

Question 31

what are the 2 other types of receptors not discussed that much in this lecture

Answer 31

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.