Chemistry and physiology of the synapse Flashcards
ACh on the heart
mAChR –>
G-protein –>
K+ channel –> hyperpolarisation
ACh on skeletal muscle
nAChR –>
Na+ channel –>
Depolarisation
Ligand gated ion channels
Responsible for fast transmission of information to the postsynaptic neuon
Ionotropic receptors
Opened by ligand binding rather than voltage change
Ligand= neurotransmitter
Allows influx of ions through central pore
Fast synaptic transmission: glutamate
Flux Na+
Excitatory post synaptic potential
Depolarises postsynaptic neurone
Threshold met causes action potential
Fast synaptic transmission: GABA
Flux Cl-
Inhibitory post synaptic potential
Hyperopolarises postsynaptic neurone
Inhibits neurone firing unless sufficient glutamate to counteract
Nicotinic
Most well studied ionotropic receptors
Activation by ACh causes excitation and contraction of muscle cells
Three types of glutamate receptors
NMDA
AMPA
Kainate
Names based on the agonists selective for them
NMDA receptors
Agonist: NMDA
Antagonist: APV
AMPA rececptors
Agonist: AMPA
Antagonist: CNQX
Kainate receptors
Agonist: kainic acid
Antagonist: CNQX
No-NMDA receptors
Fast opening channels permeable to Na+ and K+
Responsible for early phase of EPSP
NMDA receptor
Slow opening channel permeable to Ca2+, Na+ and K+
Requires extracellular glycine as cofactor to open the channel
Gated by membrane voltage
- Mg2+ plugs pore at resting potential
- membrane depolarises so Mg2+ ejected allowing conductance
Responsible for late phase ESPS
NMDA receptors- regulation of channel opening
Influx of Ca2+ as well as Na+ leads to activation of a number of enzymes and other cellular events
Cause widespread changes to postsynaptic cell
Action of NDMA receptors and resultant neuroplasticity may be molecular mechanisms that leads to long term memory formation
NMDA receptors and schizophrenia
NDMA receptors also inhibited by phencyclidine and MN801
Both bind in the open pore
Blockade produces symptoms that resemble hallucinations associated with schizophrenia
Glutamate excitotoxicity
Excessive Ca2+ influx into cell activates calcium dependent enzymes that degrade proteins, lipids and nucleic acids
Occurs after cardiac arrest, stroke, oxygen deficiency and repeated intense seizures
Glutamate
Excitatory
GABA
Inhibitory
brain
Glycine
Inhibitory
spinal cord and brain stem
Nicotine
Excitatory at NMJ
Excitatory or modulatory in CNS
Serotonin
Excitatory or modulatory
ATP
Excitatory
Metabotropic receptors
Transduce signals into cell not directly though an ion channel but through G-protein which triggers series of intracellular events
GPCR
Seven transmembrane domain protein
Transmitter binds to extracellular domain
Binding triggers uncoupling of heteromeric G protein on intracellular surface
Transduces signal across cell membrane
G proteins
- In resting state heteromer bound to GDP
- On binding of ligand to receptor, GDP switched for GTP and heteromer splits
- Ga subunit and GBy divide and diffuse separately through membrane
- Stimulate activities of other effector proteins
Alpha subunit
Gs- stimulates adenylyl cyclase
Gi- inhibits adenylyl cyclase
Gq- stimulates phospholipase C
Beta gamma complexes
Activate K+ channels directly
Mode of action for muscarinic ACh receptors in heart and GABA receptor
Second messenger cascade: cAMP
Gs and Gi have opposite effects on adenylyl cyclase
Stimulate or inhibit synthesis of cAMP and subsequent activation of protein kinase A
Second messenger cascade: PIP2
Gq activates phospholipase C
Converts PIP2 to IP3 and DAG
DAG activates protein kinase C and IP3 releases Ca2+ from internal stores
Activates Ca2+ dependent enzymes
Kinases and phosphatases
Activity of many protein regulated by phosphorylation state
Maintenance of phosphorylation an important level of control
Kinase adds phosphate
Phosphatase removes
Amplification of G protein signals
G protein signalling provides method of amplifying signals between neurones
One transmitter bound to receptor can uncouple multiple G-protein heteromers
Signal can be amplified at every stage
Weak signal at synapse can cause amplified response in postsynaptic cell
Presynaptic: Autoreceptors
Regulate release of transmitter by modulating its synthesis, release or reuptake
e.g. phosphorylation of tryosine hydroxylase
Presynaptic: Heteroreceptors
Regulate synthesis and/ or release of transmitters other than their own ligand
e.e. NE can influence release of ACh by modulating a-adrenergic receptors
Postsynaptic receptors
Change firing pattern of activity
Increase or decrease rate of cell firing
Long term synaptic changes
Metabotropic receptors
Metabotropic glutamate receptors
GABA(b) receptor
Muscarinic acetylcholine receptors
Dopamine receptors
Noradrenergic and adrenergic receptors
Serotonin receptors
Neuropeptide recetors
Enzyme linked receptors
e.g. receptor tyrosine kinases
Transmembrane proteins with intrinsic tyrosine kinase activity
Activated by neurotrophin binding
On activation autophosphorylate
Other receptors in neurones
Membrane permanent signalling molecules activate intracellular signals
e.g. NO
