L06, 07 - Neurotransmitters Flashcards
Describe the structure of electrical synapses and how signal is transduced?
Gap junction channels link presynaptic and postsynaptic membrane:
6 connexins form 1 connexon
> > pores to allow ionic current to pass through down potential difference
3 physiological functions of electrical synapses?
1) No delay = minimize time between stimulus and response
2) Synchronize electrical activity among neurons: e.g. coordinate hormone secretion with neuronal activity
3) Coordinate/ relay intracellular signalling: allow ATP, secondary messengers to pass through
Electrical synapse only allows transduction of signal in one direction. T or F?
False
Most gap junctions allow bidirectional flow
List the sequence of events that occur in chemical synapse signal transduction?
- Transmitter molecules (e.g. glutamate, GABA) are synthesized, stored in synaptic vesicles
- Action potential reaches presynaptic terminal
- Presynaptic terminal depolarizes»_space; voltage-gated Ca2+ channels open
- Rapid influx of Ca2+ down concentration gradient through channels into presynaptic terminal
- Ca2+ causes vesicles to fuse with presynaptic membrane, exocytosis into synaptic celft
- Transmitter bind to postsynaptic channels, cause excitatory/ inhibitory potential, later degraded by enzymes in cleft
- Vesicular membrane endocytosed from plasma membrane
Explain why chemical synapse signal conduction has delay?
delayed ~0.5 ms – time required for:
Secretion of neurotransmitter
Diffusion of neurotransmitter
Response of the postsynaptic cell to it
Describe how quanta of neurotransmitters can lead to firing of postsynaptic action potential?
1 quanta of nuerotransmitter = 1 miniature end plate potentials (MEPPs)
Sum of MEPPs = End Plate Potential (EEP)
If EEP is over the threshold for triggering postsynaptic membrane potential = fire
How does high or low calcium concentration in the synaptic cleft influence postsynaptic AP firing?
Low extracellular [Ca]:
- No response to presynaptic depolarization, failure to trigger postsynaptic response
High extracellular [Ca]:
- Unit response remains the same (same threshold), but less failure in response of postsynaptic neuron
List 4 proteins for fusion of neurotransmitter vesicles with presynaptic membrane?
- NEM-sensitive fusion protein (NSF)
- Soluble NSF-attachment proteins (SNAPs)
- SNAP receptors (SNARE)
- Synaptotagmin
Describe how SNAP and SNARE work to facilitate neurotransmitter vesicle fusion at presynaptic membrane?
1) SNAP + NSF prime the vesicles: e.g. SNAP binds to Syanaptobrevin (SNARE) on vesicle membrane
2) SNAP on vesicle membrane bind to SNAREs on presynaptic plasma membrane: e.g. Syntaxin, SNAP-25
3) Binding forms macromolecular complex across 2 membranes»_space; docking and fusion
Describe the role of Synaptotagmin in neurotransmitter release?
- Binds to Ca in synaptic cleft and become activated
- Ca-synaptotagmin complex insert into membrane and bind to other proteins
> > final step to fuse vesicle and plasma membrane
List the 3 proteins involved in the budding and recycling of neurotransmitter vesicles in the presynaptic membrane?
- Clathrin
- Dynamin
- Synapsin
Briefly summarize the function of Clathrin in neurotransmitter vesicles?
- Coats vesicles at cytosolic side
- Can assemble into coated pits to initiate membrane budding/ endocytosis of vesicle
Briefly summarize the function of Dynamin in neurotransmitter vesicles?
- For pinching off vesicle membrane during budding endocytosis
Briefly summarize the function of Synapsin in neurotransmitter vesicles?
- Bind to synaptic vesicle and cross link with cytoskeleton
> > keep vesicle tethered without degradation for recycling
Describe the common molecular mechanism for neurotoxins to exert effect?
toxin = proteases: cleave presynaptic SNARE proteins
> > limit vesicle-plasma membrane fusion
> > limit release of neurotransmitters
MoA of Botulinum toxin?
Botox cleaves SNAP-25, synaptobrevin and syntaxin on presynaptic membrane
> > abolish neurotransmitter release at motor neurons
> > block skeletal and visceral muscles: weakness, respiratory failure, viceral motor dysfunction
MoA of tetanus toxin?
Tetanus toxin cleaves synaptobrevin
> > Blocks release of inhibitory transmitters from interneurons in spinal cord
> > loss of synaptic inhibition on spinal motor neurons
> > hyperexcitation of skeletal muscle
2 medical uses for Botox?
- Reduce dynamic wrinkles by reducing muscle tone
2. Face slimming : cause disuse atrophy of massater to slim face
MoA of α-latrotoxin?
Bind to neurexins e.g. synaptotagmin»_space; cause spontaneous vesicle fusion without Ca
Bind to CL1»_space; activate Ca-mediated intracellular signals
> > > spontaneous synaptic vesicle discharge without extracellular Ca
What is defective in Congenital myasthenic syndromes? Inheritance pattern?
Defect in Choline acetyltransferase (ChAT) = Defect in ACh synthesis (cannot transfer choline to acetate) / packaging
autosomal recessive
List some symptoms and signs of Congenital myasthenic syndrome?
episodic apnea
weakness of the eye muscle (double vision)
mouth and throat muscles (difficulty chewing or swallowing)
Treatment of Congenital myasthenic syndrome?
AChE inhibitors:
prophylactic pyridostigmine
Name one condition that causes loss of presynaptic V-gated Ca channels?
Lambert-Eaton myasthenic syndrome (LEMS)
Common complication of lung SCC
> > defective Ca influx and Ca-mediated Ach release
List 3 monoamine neurotransmitters?
Norepinephrine
Dopamine
Histamine
List 2 amino acid neurotransmitters? Precursor?
Glutamate
GABA
Glutamine and Glutamate
List 3 peptide neurotransmitters?
Endorphin
Enkephalin
Substance P
Name 2 exogenous neurtransmitters that mimic the action of glutamate and GABA?
Glutamate: Monosodium glutamate (umami)
GABA: Benzodiazepines mimic GABA action
Describe the synthesis and recycling of small neurotransmitters like Ach? think what’s made at the ER, transport, terminal
RER: synthesize enzyme e.g. choline acetyltransferase
Slow axonal transport to terminal
Synthesis and packaging of neurotransmitter at terminal
Reuptake after release
Describe the synthesis of peptide neurotransmitters?
RER: pre-propeptide and enzymes made
Microtubule transport to terminal
Enzymatic processing of pre-propeptide
Extrasynaptic degradation by proteases: no reuptake
Describe the general structure and action of ligand-gated receptors?
4 transmembrane helices or 3 transmembrane helices + pore loop
Bind to neurotransmitter»_space; conformational change»_space; multimeric ion channel open
Describe the action of nicotinic receptors?
- Ach bind to specific site
- Channel opens, allow Na+ to enter postsynaptic neuron
- Depolarization
List 3 types of ionotropic glutamate receptors?
- AMPA
- NMDA
- Kainate
List some toxins that can cause neurotransmitter blockage?
α-bungarotoxin (snake)
α-neurotoxin (cobra)
Erabutoxin (sea snake)
Curare (plant toxin)
Which ions interfere with NMDA receptor function?
Mg2+
Interferes with binding of Na+ and Ca2+ needed for depolarization
Explain how presynaptic neuron stimulation can form synaptic memory?
High-frequency stimulation of presynaptic cell
> > Increase synaptic strength
> > more AMPA receptors respond to glutamate to trigger membrane depolarization
> > long-term higher sensitivity of post-synaptic neuron
Describe the action of ionotropic GABA receptors?
- Binding of GABA to receptor
- Conformational change causes Cl- influx into postsynaptic neuron
- Hyperpolarize, inhibit postsynaptic neuron
Compare Spatial and temporal summation?
Spatial = several excitatory postsynaptic potentials (EPSPs) arrive at axon hillock simultaneously
Temporal = sum up postsynaptic potentials created in rapid succession at the same synapse
Compare the speed and length of response between ionotropic and metabotropic receptors?
Ionotropic = Rapid, short acting response
Metabotropic = Slow, prolonged response
Compare the action between ionotropic and metabotropic receptors?
Ionotropic = Ligand- gated ion channels, allow ion influx
Metabotropic = G-protein coupled receptor, require secondary messengers
Summation of Excitatory and Inhibitory post synaptic potentials (EPSP and IPSP) occur in postsynaptic neurons. T or F?
True
EPSP and IPSP are integrated together for moment-to-moment control of AP firing
