Transcript Chapter 06 - Neurotransmitter Systems

Neurotransmitter Chemistry
• Other Neurotransmitter Candidates and
Intercellular Messengers
–
ATP
• Concentrated in vesicles at many
CNS and PNS synapses (copackaged)
• 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
Transmitter-Gated Channels
• The Basic structure of Transmitter-Gated Channels
– Nicotinic Ach receptor
a2bgd (NMJ) or a3b2 (brain)
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
Transmitter-Gated Channels
• AMPAR- vs NMDAR-mediated currents
NMDAR
• Ca2+ permeable (Excitotoxicity box 6.4)
•
Mg2+ block : coincident detector
Transmitter-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
Enhances inhibition in a
subunit-specific way
•Sedatives or anticonvulsants
•Increase the duration of
channel openings
Natural modulator
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 GProtein-Coupled Receptors
(GPCRs)
–
Simple variations on a
common plan
–
Single polypeptide with
seven membranespanning alpha-helices
–
Two extracellular loops
for ligand binding and
two intracellular loops
for G-protein binding
• The Ubiquitous G-Proteins
–
Guanosine triphosphate (GTP)
binding protein
–
~20 types : convergence!
–
Mode of operations
• At resting, GDP is bound to the Ga.
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 Ga and
Gbg complex leads to the activation
of effector proteins
• Ga breaks down GTP into GDP,
setting it back to resting state by
reassociation into Gabg complex
–
Gs stimulates the activity of
effector proteins, while Gi inhibit
effectors
G-Protein-Coupled Receptors and Effectors
• G-Protein-Coupled Effector
Systems
– The Shortcut Pathway
• From receptor to Gprotein to ion
channel
• Fast : within 30-100
msec of
neurotransmitter
binding
• Localized :
Activation depends
on the diffusion of
G-protein within the
membrane
G-Protein-Coupled Receptors and
Effectors
• GPCR Effector Systems
– Second Messenger Cascades
• G-protein couples neurotransmitter with downstream enzyme
activation
• Second messenger
cascade
G-Protein-Coupled Receptors and
Effectors
• Push-pull method
– One to stimulate and one to inhibit
G-Protein-Coupled Receptors and
Effectors
– Some cascades branch
G-Protein-Coupled Receptors and
Effectors
• Signal amplification
–
Cell-wise vs. local signaling
–
Complex regulation points
: Fine tuning
–
Long-lasting changes
G-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
Divergence and Convergence
in Neurotransmitter Systems
• Divergence
– One transmitter activates
more than one receptor
subtype various
postsynaptic responses
• Convergence
– Different transmitters
converge to affect same
effector system