Chemistry and physiology of the synapse Flashcards
Briefly outline the function of ionotropic receptors.
What are the subtypes?
Ligand-gated ion channels responsible for FAST transmission of information to the postsynaptic neuron.
Binding causes conformational change that open pore (4/5 subunits) allowing influx of ion
Glutamate ionotropic receptors:
-Influx of Na+–> EPSP which if sufficient enough causes AP
GABA ionotropic receptors:
Influx of Cl- –> IPSP hyperpolarising the cell (inhibits cell from firing AP unless sufficient glutamate stimulation)
ACh, Serotonin and ATP can also activate ionotropic receptors e.g. Nicotonic receptors @NMJ activated by ACh–> excitation and contraction of muscle cells
INTEGRATION OF ALL THE CHANGES IN THE MEMBRANE POTENTIAL WILL DETERMINE WHETHER AP IS FIRED.
NMDA receptors are a type of ionotropic receptor.
What are its agonist and antagonists?
What is its function?
Which phase of the EPSP is it responsible for?
Agonist: NMDA. Antagonist: APV
Slow opening channel permeable to Ca2+, Na+ and K+
Requires an extracellular (cleft) glycine as a cofactor to open the pore at RMP.
It is also gated by membrane voltage – Mg2+ ion plugs pore at resting membrane potentials. When membrane depolarises Mg2+ ejected from channel by electrostatic repulsion allowing conductance of other cations (ACTIVITY DEPENDENT SYNAPTIC MODIFICATION)
Responsible for a late phase EPSP
-Activated only in an already depolarised membrane in the presence of glutamate
Outline the regulation of NMDA channel opening
In presence of AMPA or NMDA antagonist, there is slower kinetics of NMDA channel (reason for late phase EPSP)
Describe the concept of neuroplasticity in regards to NMDA receptors
A widespread of cellular changes occur in the post-SN as a result of influx of Ca2+ and Na+ which activate numerous enzymes.
This resultant neuroplasticity is likely molecular mechanism for LT memory formations
CLINICAL APPLICATION
Dysregulation of NMDA receptors can have neurological effects on a patient.
What happens in inhibition of the receptor by PCP(angel dust) and MK801?
What happens in glutamate excitotoxicity?
Both bind to open pore, causing blockade. This produces symptoms that resemble schizophrenia i.e. hallucinations
**Certain antipsychotic drugs enhance current flow through NMDA
Excessive Ca2+ influx into cell activates Ca2+-dependent enzymes that degrade proteins, lipids and nucleic acids. This causes cell damage after cardiac arrest, stroke, O2 deficiency and repeated intense seizures (status epilepticus)
AMPA and Kainate receptors are types of ionotropic receptor.
What are their agonist and antagonists?
What are their functions?
Agonist: AMPA
Antagonist: CNQX
Agonist of Kainate: Kainic acid
Antagonist of Kainate: CNQX
Fast opening channels to Na+ and K+
Responsible for early phase EPSP
State at least 2 examples of excitatory and inhibitory ionotropic receptors not mentioned already.
EXCITATORY -Glutamate -Nicotinic (in NMJ and modulatory in CNS) -Serotonin (also modulatory) ATP
INHIBITORY
- GABA(A) (brain)
- Glycine (brains stem and spinal cord)
Outline the structure and function of metabotropic receptors.
Transduce signals into cell indirectly through G protein which leads to a series of intracellular events (can cause ion channel to open)
In resting state, heteromer is bound to GDP and not receptor pore.
NT binds to extracellular domain of 7 transmembrane protein.
Binding triggers GDP–>GTP. SWITCH ON–> uncoupling of heteromeric G protein.
Ga and Gyb complex divide and diffuse separately through membrane
After the uncoupling of the heteromeric G protein, what happens to the two complexes?
Gyb- activate K+ channels directly (G-protein gated ion channel). This is the mode of action for muscarinic ACh receptors in the heart and GABA(B) receptor
Ga stimulates effector protein which activates/inhibits various secondary messengers. Ga-subunits have intrinsic GTP-GDP enzymatic activity allowing signals to be transient. Breakdown of GTP = SWITCH OFF (Heteromer recomplexes and awaits activation by ligand binding to NT
Consider the action of the Ga subunit. When the binding neurotransmitter is NOREPINEPHRINE
What is its receptor? Which G protein is activated? Effector proteins? 2nd messenger? Later effector? Target action?
RECEPTOR: B-Adrenergic G-protein: Gs Effector protein: Activates Guanylyl 2nd Messenger: Activates cAMP Later effector: Protein kinase A Target action: Increase protein phosphorylation
Consider the action of the Ga subunit. When the binding neurotransmitter is GLUTAMATE
What is its receptor? Which G protein is activated? Effector proteins? 2nd messenger? Later effector? Target action?
RECEPTOR: mGluR
G-protein: Gq
Effector protein: Phospholipase C (converts PIP2 to DAG and IP3)
2nd Messenger: DAG , IP3
Later effector: Protein kinase C, Ca2+ release (activates ca2+-dependent enzymes)
Target action: Increase protein phosphorylation and activates ca2+-binding proteins
Consider the action of the Ga subunit. When the binding neurotransmitter is DOPAMINE
What is its receptor? Which G protein is activated? Effector proteins? 2nd messenger? Later effector? Target action?
RECEPTOR: D2
G-protein: Gi
Effector protein: Inhibits Guanylyl
2nd Messenger: Inhibits cAMP
Later effector: Downregulates Protein kinase A
Target action: Decrease protein phosphorylation
How are kinases and phosphatases regulated?
Intracellular 2nd messengers
Activity of many proteins regulated by their phosporylation state e.g. Phosphorylation gated channels influence membrane potentials and affect excitation state
What kind of effects do NT’s have?
The SAME NT can have both short and long term effects on an ion channel. Long term synaptic changes include structural and biochemical recruitement of new receptors/
How do G-proteins amplify a signal?
1 NT bound receptor can uncouple multiple G-protein heteromers.
