Chemistry and Physiology of the Synapse

Question 1

what are the 2 types of postsynaptic recepetors?

Answer 1

ionotropic and metabotropic

Question 2

what are ionotropic receptors?

Answer 2

ligand gated ion channels = responsible for fast transmission of information to postsynaptic neuron
channels are made up of 2/4 subunits which fold together to form a central pore
similar to voltage gated Na+ and K+ channels, but open to ligand binding, rather than voltage changes

Question 3

what do ligands do?

Answer 3

neurotransmitter
binds to channel, changing its conformation
opens channel, allowing ions to flux through the central pore

Question 4

receptor variation: pharmacology

Answer 4

what transmitter binds to the receptor and how drugs interact with them

Question 5

receptor variation: agonist

Answer 5

a drug that can combine with a receptor on a cell to produce a physiological reaction

Question 6

receptor variation: antagonist

Answer 6

a drug which blocks the activity of the agonist/endogenous ligand (neurotransmitter)

Question 7

receptor variation: kinetics

Answer 7

rate of transmitted binding and channel gating determining duration of their effects

Question 8

receptor variation: selectivity

Answer 8

which ions are fluxed

Question 9

receptor variation: conductance

Answer 9

the rate of flux helps determine effect magnitude

Question 10

what do glutamate ionotropic receptors do?

Answer 10

in general, flux Na+
cause EPSP (excitatory post synaptic potential)
depolarises postsynaptic neuron
if enough occurs, post synaptic neuron will fire an AP

Question 11

what do GABA ionotropic receptors do?

Answer 11

flux Cl-
cause IPSP (inhibitory post synaptic potential)
hyperpolarises postsynaptic neuron
inhibits neuron from firing UNLESS there is sufficient glutamate stimulation to counteract hyperpolarisation

Question 12

which are the most well studied ionotropic receptors?

Answer 12

nicotinic receptors at NMJ
activated by acetylcholine
causes excitation and contraction of muscle cells

Question 13

what can activate ionotropic recpetors?

Answer 13

glutamate
GABA
acetylcholine
serotonin
ATP

Question 14

what is the relevance of synaptic integration?

Answer 14

determines whether or not a postsynaptic neuron will fire an AP or not
summation of all excitatory and inhibitory signals - depolarisation must surpass threshold

Question 15

types of glutamate ionotropic receptors

Answer 15

NDMA
AMPA
Kainate
names based on agonists selective for them (NMDA, AMPA, Kainic acid)

Question 16

non-NMDA receptors (AMPA and Kainate) selectivity and conductance

Answer 16

fast opening channels
permeable to Na+ and K+
responsible for early phase EPSP

Question 17

NMDA receptor selectivity and conductance

Answer 17

slow opening channel
permeable to Na+, K+ and Ca2+
requires extracellular glycine as a cofactor to open the channel
gated by membrane voltage - Mg2+ plugs pore - ejected on depolarisation
responsible for late phase EPSP

Question 18

how is Mg2+ related to NMDA receptors?

Answer 18

plugs pore at resting state
on membrane depolarisation, Mg2+ is ejected by electrostatic repulsion
allows for conductance of other cations
= activity dependent synaptic modification

Question 19

how is NMDA channel opening regulated?

Answer 19

EPSPs are measure from resting potential higher than Mg2+ blockade, regardless of antagonist being present (or not)influx Ca2+ and Na+, leading to activation of enzymes and other cellular events, causing widespread changes

Question 20

which channel may be responsible for memory?

Answer 20

NMDA receptors + resultant neuroplasticity may be the molecular mechanism which leads to long term memory formation

Question 21

which conditions can result from NMDA receptor dysregulation?

Answer 21

schizophrenia, glutamate excitotoxicity

Question 22

how are schizophrenia and NMDA recpetors related?

Answer 22

NMDA receptors are inhibited by PCP and MK801
blockage of NMDA receptors produced symptoms resembling hallucinations associated with schizophrenia
certain antipsychotic drugs enhance current flow through NMDA channels

Question 23

how are NMDA receptors and glutamate excitotoxicity related?

Answer 23

excessive Ca2+ influx into cell activates calcium-dependent enzymes
degrade proteins, lipids and nucleic acids
occurs after cardiac arrest, stroke, oxygen deficiency, repeated intense seizures

Question 24

ionotropic receptors: examples

Answer 24

glutamate - excitatory GABA - inhibitory (brain)
glycine - inhibitory (spinal cord and brain stem)
nicotine - excitatory at NMJ, excitatory or modulalatory in CNS
serotonin - excitatory or modulatory
ATP - excitatory

Question 25

what are metabotropic receptors?

Answer 25

transduce signals into cell, not directly through an ion channel activate G-protein, triggers series of intracellular events, leading to ion channel opening

Question 26

what are G-protein coupled receptors?

Answer 26

seven transmembrane domain protein | multiple receptors described for every neurotransmiter

Question 27

how do G-protein coupled receptors work?

Answer 27

transmitter binds to extracellular domain of receptor binding triggers uncoupling of heteromeric G-protein on intracellular cell surface signal is transduced across cell membrane

Question 28

noradrenaline second messenger system

Answer 28

NE binds to beta-adrenergic receptor, coupled with Gs Gs activates adenylyl cyclase, which activates cAMP cAMP activates protein kinase A protein phosphorylation increases

Question 29

glutamate second messenger system

Answer 29

glutamate binds to metabotropic glutamate receptor, coupled with Gq Gq activates phospholipase C Phospholipase C converts PIP2 to diacylglycerol (activates protein kinase C) and IP3 (causes Ca2+ release) protein phosphorylation increases and calcium-binding proteins are activated

Question 30

dopamine second messenger system

Answer 30

dopamine binds to D2 dopamine receptor coupled with Gi Gi inhibits andenylyl cyclase cAMP is not activated,, so cannot activate protein kinase A protein phosphorylation decreases

Question 31

what are G proteins?

Answer 31

GTP binding proteins of 3 subunits: alpha, beta, gamma

Question 32

activity of G proteins

Answer 32

in resting state, is bound to GDP when ligand binds to receptor, GDP is swapped for GTP, causing heteromer to split in 2 G-alpha subunit and G-beta-gamma complex divide, diffusing separately through membrane individual entities stimulate activity of other effector proteins alpha subunits have intrinsic GTP-GSP activity - allows signal to be transient (breakdown from GTP to GDP switched off activity) hereromer recomplexes and awaits activation by ligand binding to another receptor

Question 33

alpha subunits of G-proteins

Answer 33

~20 Gs: stimulates adenylyl cyclase Gi: inhibits adenylyl cyclase Gq: stimulates phospholipase C

Question 34

beta-gamma complexes of G-proteins

Answer 34

5 beta, 12 gamma activate K+ channels directly (G-protein gated ion channel) = mode of action for muscarinic ACh receptors in heart and GABA receptor relatively fast acting and local effect - 'shortcut pathway'

Question 35

what is the shortcut pathway?

Answer 35

receptor - G-protein - ion channel signal binds to receptor, causing ADP to be swapped for ATP on G-protein G protein splits beta-gamma complex directly activates ion channel - no other chemical intermediates

Question 36

what is the cAMP second messenger cascade?

Answer 36

Gs and Gi have opposite effects on adenylyl cyclase stimulate or inhibit cAMP synthesis affects subsequent activation of protein kinase A

Question 37

what is the PIP2 second messenger cascade?

Answer 37

Gq activates phospholipase C (PLC) PLC converts PIP2 to IP3 and diacyglycerol (DAG) DAG ativates protein kinase C IP3 releases Va2+ from internal stores, activating Ca2+ dependent enzymes

Question 38

why are kinases and phosphatases important?

Answer 38

activity of many proteins depends on phosphorylation state kinases and phosphatases regulate by variety of intracellular second messengers e.g. phosphorylation gate channels - influences membrane potentials and excitation state

Question 39

how can G protein signals be amplified?

Answer 39

G protein signalling can amplify signals between neurons one transmitter bound receptor can uncouple multiple G-protein heteromers signal can be amplified at each stage weak signals can hence cause an amplified response in the postsynaptic cell

Question 40

how can presynaptic receptor activation modulate activity?

Answer 40

change the amount of transmitter released autoreceptors: regulate release of transmitter by modulating its: synthesis, storage, release or reuptake e. g. phosphorylation of tyrosine hydroxylase heteroreceptors: regulate synthesis and/or release of transmitters other than their own ligand e. g. NE can influence release of ACh by modulating alpha-adrenergic receptors

Question 41

how can postsynaptic receptor activation modulate activity

Answer 41

change firing pattern or activity increase/decrease rate of cell firing (directly by action at ligand gate ion channels, or indirectly at G-protein/phosphorylation coupled channels or long term changes

Question 42

metabotropic receptors: examples

Answer 42

``` metabotropic glutamate receptors - Group I (Gq), II (Gi) and III (Gi) GABA(b) receptor muscarinic ACh recpetors dopamine receptors noradrenergic and adrenergic receptors serotonin receptors neuropeptide receptors ```

Question 43

other receptors found on or in neurons

Answer 43

enzyme linked receptors eg receptor tyrosine kinases = transmembrane proteins with intrinsic tyrosine kinase activity activated by neurotrophin binding autophosphorylate on activation: phosphorylate regulatory subunits signal transduction cascades membrane permanent signalling molecules - activate intracellular receptors