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

Transmitter-Gated Channels Transmitter-Gated Channels

• The Basic structure of Transmitter-Gated Channels

– Nicotinic Ach receptor

NMJ) or (brain)

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

Transmitter-Gated Channels Transmitter-Gated Channels

• AMPAR- vs NMDAR-mediated currents

NMDAR• Ca2+ permeable (Excitotoxicity box 6.4)• Mg2+ block : coincident detector

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

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

• 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

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

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

G-Protein-Coupled Receptors and EffectorsG-Protein-Coupled Receptors and Effectors

• Push-pull method

– One to stimulate and one to inhibit

G-Protein-Coupled Receptors and EffectorsG-Protein-Coupled Receptors and Effectors

– Some cascades branch

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

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

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