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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