Neurotransmitter Systems Overview: Study of Receptors, Localization, and Chemistry

1. Neuroscience: Exploring the Brain, 3e Chapter 6: Neurotransmitter Systems

2. 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. 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. Studying Neurotransmitter Systems • Studying Transmitter Localization • Transmitters and Transmitter-Synthesizing Enzymes • Immunocytochemistry – localize molecules to cells

5. Studying Neurotransmitter Systems • Studying Transmitter Localization (Cont’d) • In situ hybridization • Localize synthesis of protein or peptide to a cell (detect mRNA)

6. 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. 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. Studying Neurotransmitter Systems • Studying Receptor Subtypes • Neuropharmacology • Agonists and antagonists • e.g., ACh receptors • Nicotinic, Muscarinic • Glutamate receptors • AMPA, NMDA, and kainite

9. Studying Neurotransmitter Systems • Studying Receptors (Cont’d) • Ligand-binding methods • Identify natural receptors using radioactive ligands • Can be: Agonist, antagonist, or chemical neurotransmitter

10. 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. Neurotransmitter Chemistry • Evolution of neurotransmitters • Neurotransmitter molecules • Amino acids, amines, and peptides • Dale’s Principle • Oneneuron, one neurotransmitter • Co-transmitters • Two or more transmitters released from one nerve terminal • An amino acid or amine plus a peptide

12. Neurotransmitter Chemistry • Cholinergic (ACh) Neurons

13. Neurotransmitter Chemistry • Cholinergic (ACh) Neurons

14. 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. 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. 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

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

19. 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. Transmitter-Gated Channels • The Basic Structure of Transmitter-Gated Channels • Pentamer: Five protein subunits

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

24. Transmitter-Gated Channels • Amino Acid-Gated Channels • Voltage dependent NMDA channels

25. 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. 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. G-Protein-Coupled Receptors and Effectors • The Ubiquitous G-Proteins • GTP-binding (G-) protein • Signal from receptor to effector proteins

28. 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. G-Protein-Coupled Receptors and Effectors • GPCR Effector Systems • The Shortcut Pathway • From receptor to G-protein to ion channel; Fast and local

30. G-Protein-Coupled Receptors and Effectors • GPCR Effector Systems • Second Messenger Cascades • G-protein: Couples neurotransmitter with downstream enzyme activation

31. 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. 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. G-Protein-Coupled Receptors and Effectors • GPCR Effector Systems (Cont’d) • Signal amplification

34. 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. Divergence and Convergencein Neurotransmitter Systems • Divergence • One transmitter activates more than one receptor subtype greater postsynaptic response • Convergence • Different transmitters converge to affect same effector system

36. 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. End of Presentation