Protein Coupled Receptors and Effectors

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					       Neurotransmitter 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
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


                                               •Sedatives or anticonvulsants
•Diazepam or valium
                                               •Increase the duration of
•Increase the frequency of
                                               channel openings
channel openings



Enhances inhibition in a                       Natural modulator
subunit-specific way
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
• 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 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
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

				
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posted:10/25/2012
language:English
pages:18