Neurotransmitter

1. Neurotransmitter Su Bo Institute of neurobiology 0531-88382329; bxs103@sdu.edu.cn

2. Outline • Neurotransmitter categories • Neurotransmitter chemistry • Some important neurotransmitters

3. Discovery of Neurotransmitter 1936 Nobel prize winner • 1904, Renton Elliott, hypothesis neurotransmitter; • 1914, Henry Dale discovered acetylcholine; • stimulation of the parasympathetic nervous system; • 1920, Otto Loewi (奥托洛维) ; • 1929 Dale purified acetylcholine from mammalian organs

4. Basic Concepts of NT • Neurotransmitter递质 Endogenous signaling molecules that alter the behaviour of neurons or effector cells. • Neuromodulator调质 Endogenous signaling molecules that regulate the behaviour of neurons or effector cells.

5. Criteria for neurotransmitter • The molecule must be synthesized and stored in the presynaptic neuron. • The molecule must be released by the presynaptic axon terminal upon stimulation. • The molecule ,when experimentally applied, must produce a response in the postsynaptic cell that mimics the response produced by the release of neurotransmitter from the presynaptic neuron.

6. Categories of neurotransmitters

8. Neuropeptides

9. Outline • Neurotransmitter categories • Neurotransmitter chemistry • Some important neurotransmitters

10. Elements of Neurotransmitter System

11. Neuropeptide Small-molecule neurotransmitter Synthesis

12. Vesicular transporter • ATP-dependent H+ accumulation • Reverse transport • Vesicular ACh transporter (VAChT) • Vesicular monoamine transporter (VMAT) • Vesicular Glu transporter (VGLUT) • Vesicular inhibitory amino acid transporter (VIAAT)

13. Storage small clear-core vesicles 40-60nm large dense-core vesicles 90-250nm Neuropeptides, Amines Ach, Amino acids

14. 囊泡储存是递质储存的主要方式 • 递质合成后储存在囊泡内，囊泡内可以有数千个递质分子。待释放的活动囊泡聚集在突触前膜活动区，为递质的胞裂外排作好准备 • 小分子递质如乙酰胆碱、氨基酸类递质储存在直径40~60 nm的小囊泡中，在电镜下囊泡中央清亮，为小的清亮囊泡 • 神经肽储存在直径约90~250nm的大囊泡中，电镜下，囊泡中央电子密度较高，为大的致密核心囊泡 • 单胺类递质储存的囊泡既有小的致密核心囊泡，也有大的（直径60~120 nm）不规则形状的致密囊泡

15. Neurotransmitter Co-existence • Dale’s principle: A neuron has only one neurotransmitter. • Both a classical neurotransmitter (ACh or catecholamine) and a polypeptide neurotransmitter exist in the terminal of one neurons. • They are contained in different synaptic vesicles that can be distinguished using the electron microscope. • The neuron can thus release either the classical neurotransmitter or the polypeptide neurotransmitter under different conditions.

16. Cotransmission • Cotransmissionis the release of several types of neurotransmitters from a single nerve terminal. • Some neurons can release at least two neurotransmitters at the same time, the other being a cotransmitter, in order to provide the stabilizing negative feedback required for meaningful encoding, in the absence of inhibitory interneurons. • GABA–glycine co-release. • Dopamine–glutamate co-release. • Acetylcholine–glutamate co-release. • Glutamate–dynorphin co-release

17. Release fast 300us slow 50ms

18. Ca2+ dependent Release

19. Ca2+ dependent release Fura-2 staining

20. Tetanus

21. Lambert-Eaton myasthenic syndrome(LEMS)

22. Transmitter Termination • Diffusion • Reuptake • Enzymatic degradation: neuropeptides • Autoreceptor • Combination of above

23. Reuptake • Transporter exist in the presynaptic membrane or the membrane of glia surrounding the synapse • Na+/K+-dependent transporter：Glutamate • Na+/Cl--dependent transporter: GABA, Amines

24. Two Families of Postsynaptic Receptors • Transmitter-gated ion channels • directly controls channel • fast • G-protein-coupled receptors • second messenger systems • receptor indirectly controls channel • slow

25. Transmitter-gated ion channels

26. The general architecture of ligand-gated receptors • One of the subunits of a complete receptor • Assembly of either four or five subunits into a complete receptor

28. A diversity of subunits come together to form functional ionotropic receptors

29. The basic structure of GPCR

30. Structure of GPCRs

31. Structure of GPCRs These receptor proteins contain seven transmembrane domains. Portions of domains II, III, VI, and VII make up the neurotransmitter-binding region. G-proteins bind to both the loop between domains V and VI and to portions of the C-terminal region.

32. G-protein-coupled receptors

33. The basic mode of operation of G-proteins

34. The basic mode of operation of G-proteins

36. Gs/Gi－AC－cAMP

37. 细胞膜 Gs AC 2cAMP R R C C + C C 2cAMP R R 核 膜 ATP cAMP

38. Pi Pi Pi Pi Ｃ Ｒ Ｅ Ｂ Ｃ Ｒ Ｅ Ｂ 生理效应 Ｃ Ｃ 细胞核 Ｃ Ｒ Ｅ Ｂ Ｃ Ｒ Ｅ Ｂ DNA ＣＲＥ 结构基因 蛋白质

39. QIAGEN

40. Gq-PLC-IP3/DAG

41. Varieties of metabotropic neurotransmitter receptors

43. Agonist and Antagonist • Each neurotransmitter exerts its postsynaptic effects by binding to specific receptors. • Neuropharmacological analysis: studying different receptor subtypes using agonist and antagonist.

44. Agonist • A substance that mimics a specific neurotransmitter, is able to attach to that neurotransmitter's receptor and thereby produces the same action that the neurotransmitter usually produces. • Drugs are often designed as receptor agonists to treat a variety of diseases and disorders when the original chemical substance is missing or depleted.

45. Antagonist • Drugs that bind to but do not activate neuroreceptors, thereby blocking the actions of neurotransmitters or the neuroreceptor agonists.

46. Neuropharmacology of Receptor Subtypes

47. Neurotransmitter chemistry

48. Outline • Neurotransmitter categories • Neurotransmitter chemistry • Some important neurotransmitters

49. Acetylcholine (ACh)

50. ACh system • Arising from the basal forebrain (基底前脑) and brain stem (脑干) • The medial septal nuclei (隔内侧核) and basal nucleus of Meynert project widely upon the cerebral cortex (hippocampus) • The pontomesencephalo-tegmental complex (脑桥-中脑-被盖复合体)projects to the thalamus and parts of the forebrain