| Synaptic Events (Linden & Lloyd) | Neurotrasmitters (Baraban & Snyder) | GPCRs, 2nd Messengers, and Phosphorylation (Margolis & Zhaozhu) | Myelination and Voltage-gated channels (Calabresi & Bosmans) |
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The blockage of voltage-gated Na channels (with TTX) and voltage-gated K channels (with TEA) did not prevent synaptic transmission at the NMJ. However, a Ca-free medium did prevent transmission, and this was rescued by puffing Ca just before, but not after, stimulation.
Describe the experiments showing that Ca, but not Na or K, is required for converting an action potential at the presynaptic terminal to synaptic transmission.
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Neurons are independent units: “contiguous but not continuous”
Dynamic polarization – information flows in one direction from dendrites to axons Unidirectional flow of information between neurons at “gaps”, now called synapses
What is the "neuron doctrine"?
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DAG is membrane-bound and activates PKC. IP3 binds receptors on the ER and triggers Ca release into the cytosol.
Name the two second messengers derived from PIP2 and what their downstream effects are.
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demylelination: destruction of myelin sheath
dysmyelination: disruption in myelin formation and maintenance
What are demyelination and dysmyelination?
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The high thermodynamic favorability of the conversion of trans-SNAREs to cis-SNAREs provides the energy to drive vesicular fusion.
-Synaptotagmin -Complexin -SM (Sec1/Munc18) -NSF/alpha-SNAP
Describe how SNARE proteins drive vesicular fusion and name one protein involved in regulating their function.
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Biogenic Amines-Dopamine, Norepinephrine, and Serotonin
Amino Acids-GABA, Glycine Peptides-Oxytocin, Beta Endorphin
Name the three main classes of Neurotransmitters. Give an example molecule for each class.
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Arrestins bind with the phosphorylated regions of GPCR to block further protein interaction and to recruit proteins for receptor internalization
What is the role of arrestin in GPCR desensitization?
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(tetramer vs. monomer, selectivity filter: size and dehydration, inactivation: ball/chain vs hinged lid , kinetics: slow vs. fast)
Name three differences between Kv and Nav
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A RIM knockout would show an impairment in vesicular association with the presynaptic membrane. A synaptotagmin knockout would have vesicles bound and primed but incapable of release.
What specific impairments of vesicular release would you expect in a RIM knockout? Synaptotagmin knockout?
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-Lack of expression of dopamine beta-hydroxylase
-Expression of DAT -Altered postsynaptic responses in presence of dopamine receptor agonists/antagonists
How might you verify that a neuron expressing tyrosine hydroxylase is dopaminergic as opposed to adrenergic?
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Phosphorylation adds a large negative charge that alters protein conformation and thereby function. Processes include:
-Signal transduction -Synaptic transmission -Electrical excitability -Transcription/translation
Describe why phosphorylation alters protein function. What are some processes phosphorylation is important for?
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voltage sensor, gate, selectivity filter, inactivation domain
Draw an α subunit of voltage-gated potassium channel (Kv) and describe the functions of the components
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>> AMPA: fast-on and fast-off; NMDA: slow-on and slow-off
>> NMDA is blocked by Mg2+, but AMPA doesn’t. >> AMPA is permeable to Na+ and K+ but not Ca2+. NMDA is Ca2+ permeable.
Describe the differences between NMDA and AMPA receptors
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-Ionotropic vs metabotropic receptors
-Coupling to different G-proteins -Varying affinities for the ligand
Describe some of the ways in which different effects are achieved by a single neurotransmitter.
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>> GPCR do not have a channel.
>> GPCR act slowly but generate longer lasting changes. >> Multiple steps involved in signal amplification including G-protein, 2nd messengers, protein phosphorylation.
Describe some important features of GPCR that are different from ionotropic receptors.
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Nav1.2/beta 1-> fast inactivation, Nav1.2/ beta 4 -> no response to ProTX-II
Give one example that can demonstrate auxiliary subunits influence voltage-gated ion channel functions
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In low Ca and high Mg to reduce the number of events at the NMJ, Katz found that spontaneous mEPPs had a unimodal distribution and evoked events had a multimodal distribution with peaks at multiples of the mEPP amplitude.
Describe how Katz determined that neurotransmitter release is quantal.
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The postsynaptic neuron might express metabotropic ACh receptors, which are not sensitive to curare.
You apply curare while stimulating cholinergic neurons but observe no difference in synaptic transmission. What might be the reason?
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Norepinephrine binds the beta-adrenergic receptor
Receptor-associated Gs is activated Gs activates adenylyl cyclase Adenylyl cyclase generates cAMP cAMP binds regulatory subunits of PKA to liberate catalytic domains
Outline how protein kinase A is activated, starting from a neurotransmitter binding a particular receptor.
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>> Animal models: Shiverer (deletion of a part of MBP gene), Jimpy (mutation in PLP gene), EAE (autoimmune problem)
>> Diseases: Leukodystrophies (genetic factor, dysmyelination), Multiple Sclerosis (genetic, environment, immune factors, demyelination) , Progressive Multifocal Leukoencephalopathy (PML, JC virus infection), Subacute Combined Degeneration (vitamin B12 deficiency) >> Axon degeneration, deficits in impulse propagation, mitochondria dysfunction, Nav redistribution, vulnerable to ionic stress
Describe two animal models/ diseases related to demyelination or dysmyelination
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