1. Copyright © 2007 Wolters Kluwer Health | Lippincott Williams & Wilkins Neuroscience: Exploring the Brain, 3e Chapter 6: Neurotransmitter Systems

2. Copyright © 2007 Wolters Kluwer Health | Lippincott Williams & Wilkins Introduction Three classes of neurotransmitters –Amino acids, amines, and peptides Many different neurotransmitters Defining particular transmitter systems –By the molecule, synthetic machinery, packaging, reuptake and degradation, etc. Acetylcholine (Ach) – First identified neurotransmitter Nomenclature (-ergic) –Cholinergic and noradrenergic

3. Copyright © 2007 Wolters Kluwer Health | Lippincott Williams & Wilkins Studying Neurotransmitter Systems Neurotransmitter - three criteria –Synthesis and storage in presynaptic neuron –Released by presynaptic axon terminal –Produces response in postsynaptic cell Mimics response produced by release of neurotransmitter from the presynaptic neuron

4. Copyright © 2007 Wolters Kluwer Health | Lippincott Williams & Wilkins Studying Neurotransmitter Systems Studying Transmitter Localization –Transmitters and Transmitter-Synthesizing Enzymes Immunocytochemistry – localize molecules to cells

5. Copyright © 2007 Wolters Kluwer Health | Lippincott Williams & Wilkins Studying Neurotransmitter Systems Studying Transmitter Localization (Cont’d) In situ hybridization Localize synthesis of protein or peptide to a cell (detect mRNA)

6. Copyright © 2007 Wolters Kluwer Health | Lippincott Williams & Wilkins Studying Neurotransmitter Systems Studying Transmitter Release –Transmitter candidate: Synthesized and localized in terminal and released upon stimulation –CNS contains a diverse mixture of synapses that use different neurotransmitters –Brain slice as a model Kept alive in vitro  Stimulate synapses, collect and measure released chemicals

7. Copyright © 2007 Wolters Kluwer Health | Lippincott Williams & Wilkins Studying Neurotransmitter Systems Studying Synaptic Mimicry –Qualifying condition: Molecules evoking same response as neurotransmitters –Microionophoresis: Assess the postsynaptic actions –Microelectrode: Measures effects on membrane potential

8. Copyright © 2007 Wolters Kluwer Health | Lippincott Williams & Wilkins Studying Neurotransmitter Systems Studying Receptor Subtypes –Neuropharmacology Agonists and antagonists e.g., ACh receptors Nicotinic, Muscarinic Glutamate receptors AMPA, NMDA, and kainite

9. Copyright © 2007 Wolters Kluwer Health | Lippincott Williams & Wilkins Studying Neurotransmitter Systems Studying Receptors (Cont’d) –Ligand-binding methods Identify natural receptors using radioactive ligands Can be: Agonist, antagonist, or chemical neurotransmitter

10. Copyright © 2007 Wolters Kluwer Health | Lippincott Williams & Wilkins Studying Neurotransmitter Systems Studying Receptors (Cont’d) –Molecular analysis- receptor protein classes Transmitter-gated ion channels GABA receptors 5 subunits, each made with 6 different subunit polypeptides G-protein-coupled receptors

11. Copyright © 2007 Wolters Kluwer Health | Lippincott Williams & Wilkins Neurotransmitter Chemistry Evolution of neurotransmitters –Neurotransmitter molecules Amino acids, amines, and peptides Dale’s Principle –One neuron, one neurotransmitter Co-transmitters –Two or more transmitters released from one nerve terminal –An amino acid or amine plus a peptide

12. Copyright © 2007 Wolters Kluwer Health | Lippincott Williams & Wilkins Neurotransmitter Chemistry Cholinergic (ACh) Neurons

13. Copyright © 2007 Wolters Kluwer Health | Lippincott Williams & Wilkins Neurotransmitter Chemistry Cholinergic (ACh) Neurons

14. Copyright © 2007 Wolters Kluwer Health | Lippincott Williams & Wilkins Neurotransmitter Chemistry Catecholaminergic Neurons –Involved in movement, mood, attention, and visceral function –Tyrosine: Precursor for three amine neurotransmitters that contain catechol group Dopamine (DA) Norepinephrine (NE) Epinephrine (E, adrenaline)

15. Copyright © 2007 Wolters Kluwer Health | Lippincott Williams & Wilkins Neurotransmitter Chemistry Serotonergic (5-HT) Neurons –Amine neurotransmitter Derived from tryptophan –Regulates mood, emotional behavior, sleep Selective serotonin reuptake inhibitors (SSRIs) - Antidepressants –Synthesis of serotonin

16. Copyright © 2007 Wolters Kluwer Health | Lippincott Williams & Wilkins Neurotransmitter Chemistry Amino Acidergic Neurons –Amino acidergic neurons have amino acid transporters for loading synaptic vesicles. –Glutamic acid decarboxylase (GAD) Key enzyme in GABA synthesis Good marker for GABAergic neurons GABAergic neurons are major of synaptic inhibition in the CNS

17. Copyright © 2007 Wolters Kluwer Health | Lippincott Williams & Wilkins

18. Neurotransmitter Chemistry Other Neurotransmitter Candidates and Intercellular Messengers –ATP: Excites neurons; Binds to purinergic receptors –Endocannabinoids –Retrograde messengers

19. Copyright © 2007 Wolters Kluwer Health | Lippincott Williams & Wilkins Transmitter-Gated Channels ‘Ionotropic receptors’ Introduction –Fast synaptic transmission –Sensitive detectors of chemicals and voltage –Regulate flow of large currents –Differentiate between similar ions

20. Copyright © 2007 Wolters Kluwer Health | Lippincott Williams & Wilkins Transmitter-Gated Channels The Basic Structure of Transmitter-Gated Channels –Pentamer: Five protein subunits

21. Copyright © 2007 Wolters Kluwer Health | Lippincott Williams & Wilkins

23. Transmitter-Gated Channels Amino Acid-Gated Channels –Glutamate-Gated Channels AMPA, NMDA, kainite

24. Copyright © 2007 Wolters Kluwer Health | Lippincott Williams & Wilkins Transmitter-Gated Channels Amino Acid-Gated Channels –Voltage dependent NMDA channels

25. Copyright © 2007 Wolters Kluwer Health | Lippincott Williams & Wilkins 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

26. Copyright © 2007 Wolters Kluwer Health | Lippincott Williams & Wilkins 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) –Single polypeptide with seven membrane-spanning alpha-helices

27. Copyright © 2007 Wolters Kluwer Health | Lippincott Williams & Wilkins G-Protein-Coupled Receptors and Effectors The Ubiquitous G-Proteins –GTP-binding (G-) protein –Signal  from receptor to effector proteins

28. Copyright © 2007 Wolters Kluwer Health | Lippincott Williams & Wilkins G-Protein-Coupled Receptors and Effectors The Ubiquitous G-Proteins (Cont’d) –Five steps in G-protein operation Inactive: Three subunits - , , and  - “float” in membrane (  bound to GDP) Active: Bumps into activated receptor and exchanges GDP for GTP G  -GTP and G  - Influence effector proteins G  inactivates by slowly converting GTP to GDP G  recombine with G  -GDP

29. Copyright © 2007 Wolters Kluwer Health | Lippincott Williams & Wilkins G-Protein-Coupled Receptors and Effectors GPCR Effector Systems –The Shortcut Pathway From receptor to G-protein to ion channel; Fast and local

30. Copyright © 2007 Wolters Kluwer Health | Lippincott Williams & Wilkins G-Protein-Coupled Receptors and Effectors GPCR Effector Systems –Second Messenger Cascades G-protein: Couples neurotransmitter with downstream enzyme activation

31. Copyright © 2007 Wolters Kluwer Health | Lippincott Williams & Wilkins G-Protein-Coupled Receptors and Effectors GPCR Effector Systems (Cont’d) Push-pull method (e.g., different G proteins for stimulating or inhibiting adenylyl cyclase)

32. Copyright © 2007 Wolters Kluwer Health | Lippincott Williams & Wilkins G-Protein-Coupled Receptors and Effectors GPCR Effector Systems (Cont’d) Some cascades split G-protein activates PLC  generates DAG and IP3  activate different effectors

33. Copyright © 2007 Wolters Kluwer Health | Lippincott Williams & Wilkins G-Protein-Coupled Receptors and Effectors GPCR Effector Systems (Cont’d) Signal amplification

34. Copyright © 2007 Wolters Kluwer Health | Lippincott Williams & Wilkins G-Protein-Coupled Receptors and Effectors GPCR Effector Systems (Cont’d) –Phosphorylation and Dephosphorylation Phosphate groups added to or removed from a protein Changes conformation and biological activity –The Function of Signal Cascades Signal amplification by GPCRs

35. Copyright © 2007 Wolters Kluwer Health | Lippincott Williams & Wilkins Divergence and Convergence in Neurotransmitter Systems Divergence –One transmitter activates more than one receptor subtype  greater postsynaptic response Convergence –Different transmitters converge to affect same effector system

36. Copyright © 2007 Wolters Kluwer Health | Lippincott Williams & Wilkins Concluding Remarks Neurotransmitters –Transmit information between neurons –Essential link between neurons and effector cells Signaling pathways –Signaling network within a neuron somewhat resembles brain’s neural network –Inputs vary temporally and spatially to increase and/or decrease drive –Delicately balanced –Signals regulate signals- drugs can shift the balance of signaling power

37. Copyright © 2007 Wolters Kluwer Health | Lippincott Williams & Wilkins End of Presentation