Chemistry and Physiology of the Synapse Flashcards
what are the 2 types of postsynaptic recepetors?
ionotropic and metabotropic
what are ionotropic receptors?
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
what do ligands do?
neurotransmitter
binds to channel, changing its conformation
opens channel, allowing ions to flux through the central pore
receptor variation: pharmacology
what transmitter binds to the receptor and how drugs interact with them
receptor variation: agonist
a drug that can combine with a receptor on a cell to produce a physiological reaction
receptor variation: antagonist
a drug which blocks the activity of the agonist/endogenous ligand (neurotransmitter)
receptor variation: kinetics
rate of transmitted binding and channel gating determining duration of their effects
receptor variation: selectivity
which ions are fluxed
receptor variation: conductance
the rate of flux helps determine effect magnitude
what do glutamate ionotropic receptors do?
in general, flux Na+
cause EPSP (excitatory post synaptic potential)
depolarises postsynaptic neuron
if enough occurs, post synaptic neuron will fire an AP
what do GABA ionotropic receptors do?
flux Cl-
cause IPSP (inhibitory post synaptic potential)
hyperpolarises postsynaptic neuron
inhibits neuron from firing UNLESS there is sufficient glutamate stimulation to counteract hyperpolarisation
which are the most well studied ionotropic receptors?
nicotinic receptors at NMJ
activated by acetylcholine
causes excitation and contraction of muscle cells
what can activate ionotropic recpetors?
glutamate GABA acetylcholine serotonin ATP
what is the relevance of synaptic integration?
determines whether or not a postsynaptic neuron will fire an AP or not
summation of all excitatory and inhibitory signals - depolarisation must surpass threshold
types of glutamate ionotropic receptors
NDMA
AMPA
Kainate
names based on agonists selective for them (NMDA, AMPA, Kainic acid)
non-NMDA receptors (AMPA and Kainate) selectivity and conductance
fast opening channels
permeable to Na+ and K+
responsible for early phase EPSP
NMDA receptor selectivity and conductance
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
how is Mg2+ related to NMDA receptors?
plugs pore at resting state
on membrane depolarisation, Mg2+ is ejected by electrostatic repulsion
allows for conductance of other cations
= activity dependent synaptic modification
how is NMDA channel opening regulated?
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
which channel may be responsible for memory?
NMDA receptors + resultant neuroplasticity may be the molecular mechanism which leads to long term memory formation
which conditions can result from NMDA receptor dysregulation?
schizophrenia, glutamate excitotoxicity
how are schizophrenia and NMDA recpetors related?
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
how are NMDA receptors and glutamate excitotoxicity related?
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
ionotropic receptors: examples
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
what are metabotropic receptors?
transduce signals into cell, not directly through an ion channel
activate G-protein, triggers series of intracellular events, leading to ion channel opening
what are G-protein coupled receptors?
seven transmembrane domain protein
multiple receptors described for every neurotransmiter
how do G-protein coupled receptors work?
transmitter binds to extracellular domain of receptor
binding triggers uncoupling of heteromeric G-protein on intracellular cell surface
signal is transduced across cell membrane
noradrenaline second messenger system
NE binds to beta-adrenergic receptor, coupled with Gs
Gs activates adenylyl cyclase, which activates cAMP
cAMP activates protein kinase A
protein phosphorylation increases
glutamate second messenger system
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
dopamine second messenger system
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
what are G proteins?
GTP binding proteins of 3 subunits: alpha, beta, gamma
activity of G proteins
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
alpha subunits of G-proteins
~20
Gs: stimulates adenylyl cyclase
Gi: inhibits adenylyl cyclase
Gq: stimulates phospholipase C
beta-gamma complexes of G-proteins
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’
what is the shortcut pathway?
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
what is the cAMP second messenger cascade?
Gs and Gi have opposite effects on adenylyl cyclase
stimulate or inhibit cAMP synthesis
affects subsequent activation of protein kinase A
what is the PIP2 second messenger cascade?
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
why are kinases and phosphatases important?
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
how can G protein signals be amplified?
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
how can presynaptic receptor activation modulate activity?
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
how can postsynaptic receptor activation modulate activity
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
metabotropic receptors: examples
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
other receptors found on or in neurons
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
