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 Ca 2+ -dependent manner Excites neurons by binding to purinergic receptors, some of which are transmitter-gated channels –Endocannabinoids Retrograde messengers induced by postsynaptic activity ([Ca 2+ ] ) Reduce the opening of presynaptic calcium channels

Transmitter-Gated Channels The Basic structure of Transmitter-Gated Channels –Nicotinic Ach receptor   NMJ) or     (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 Ca 2+ permeable (Excitotoxicity box 6.4) Mg 2+ 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 Sedatives or anticonvulsants Increase the duration of channel openings Enhances inhibition in a subunit-specific way 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 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 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 G  breaks 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

G-Protein-Coupled Receptors and Effectors G-Protein-Coupled Effector Systems –The Shortcut Pathway From receptor to G- protein to ion channel Fast : within 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