neurotransmitter chemistry other neurotransmitter candidates and intercellular messengers –atp...
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Neurotransmitter ChemistryNeurotransmitter Chemistry
• Other Neurotransmitter Candidates and Intercellular Messengers
– ATP
• Concentrated in vesicles at many CNS and PNS synapses (co-packaged)
• Released into cleft by presynaptic spikes in Ca2+-dependent manner
• Excites neurons by binding to purinergic receptors, some of which are transmitter-gated channels
– Endocannabinoids
• Retrograde messengers induced by postsynaptic activity ([Ca2+] )
• Reduce the opening of presynaptic calcium channels
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Transmitter-Gated Channels Transmitter-Gated Channels
• The Basic structure of Transmitter-Gated Channels
– Nicotinic Ach receptor
NMJ) or (brain)
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Transmitter-Gated Channels Transmitter-Gated Channels • Amino Acid-Gated Channels
– Mediate most of fast synaptic transmission in the CNS• Pharmacology• Kinetics• Selectivity• Conductance
– Glutamate-Gated Channels
• AMPA, NMDA, kainate
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Transmitter-Gated Channels Transmitter-Gated Channels
• AMPAR- vs NMDAR-mediated currents
NMDAR• Ca2+ permeable (Excitotoxicity box 6.4)• Mg2+ block : coincident detector
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Transmitter-Gated ChannelsTransmitter-Gated Channels
• Amino Acid-Gated Channels
– GABA-Gated and Glycine-Gated Channels
• GABA mediates inhibitory transmission
• Glycine mediates non-GABA inhibitory transmission
• Bind ethanol, benzodiazepines, barbiturates
•Diazepam or valium•Increase the frequency of channel openings
•Sedatives or anticonvulsants•Increase the duration of channel openings
Enhances inhibition in a subunit-specific way
Natural modulator
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G-Protein-Coupled Receptors and Effectors G-Protein-Coupled Receptors and Effectors
• Three steps
– Binding of the neurotransmitter to the receptor protein
– Activation of G-proteins
– Activation of effector systems • The Basic Structure of G-
Protein-Coupled Receptors (GPCRs)
– Simple variations on a common plan
– Single polypeptide with seven membrane-spanning alpha-helices
– Two extracellular loops for ligand binding and two intracellular loops for G-protein binding
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• The Ubiquitous G-Proteins
– Guanosine triphosphate (GTP) binding protein
– ~20 types : convergence!
– Mode of operations
• At resting, GDP is bound to the G.
The whole complex floats around
• When this complex bumps into the proper type of receptor that is bound to a transmitter molecule, GDP to GTP exchange occurs
• Split of the complex into G and G complex leads to the activation of effector proteins
• Gbreaks down GTP into GDP, setting it back to resting state by reassociation into G complex
– Gs stimulates the activity of effector proteins, while Gi inhibit effectors
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G-Protein-Coupled Receptors and Effectors G-Protein-Coupled Receptors and Effectors
• G-Protein-Coupled Effector Systems
– The Shortcut Pathway
• From receptor to G-protein to ion channel
• Fast : within 30-100 msec of neurotransmitter binding
• Localized : Activation depends on the diffusion of G-protein within the membrane
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G-Protein-Coupled Receptors and Effectors G-Protein-Coupled Receptors and Effectors
• GPCR Effector Systems
– Second Messenger Cascades
• G-protein couples neurotransmitter with downstream enzyme activation
• Second messenger
cascade
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G-Protein-Coupled Receptors and EffectorsG-Protein-Coupled Receptors and Effectors
• Push-pull method
– One to stimulate and one to inhibit
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G-Protein-Coupled Receptors and EffectorsG-Protein-Coupled Receptors and Effectors
– Some cascades branch
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G-Protein-Coupled Receptors and EffectorsG-Protein-Coupled Receptors and Effectors
• Signal amplification
– Cell-wise vs. local signaling
– Complex regulation points
: Fine tuning
– Long-lasting changes
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G-Protein-Coupled Receptors and EffectorsG-Protein-Coupled Receptors and Effectors
• Phosphorylation and Dephosphorylation
– Effective way to regulate protein activity (Economically)
– Slight change of conformation can bring about many different outcomes
– Balance between kinase and phosphatase activity
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Divergence and Convergencein Neurotransmitter SystemsDivergence and Convergencein Neurotransmitter Systems
• Divergence
– One transmitter activates more than one receptor subtype various postsynaptic responses
• Convergence
– Different transmitters converge to affect same effector system