Receptors & Transmitters

1. DENT/OBHS 131Neuroscience Receptors & Transmitters 2009

2. Learning Objectives • Know what criteria are used to define a neurotransmitter • Recall the major different categories of transmitters • Know the names of the principle neurotransmitters in the CNS (including: glutamate, GABA, acetylcholine, norepinephrine, serotonin and dopamine) • Compare and contrast small the synthesis and action of small molecular weight and peptide transmitters • Identify the brainstem nuclei associated with the biogenic amine transmitters • Compare and contrast ligand-gated and G-protein coupled receptors

3. You are a neurotransmitter if you…. • are produced within a neuron, and are present in the presynaptic terminal • are released during depolarization (action potential-dependent manner) • act on receptors to cause a biological effect • have a mechanism of termination

4. More strictly, to be a transmitter.. • a particular substance, when applied to the post-synaptic cell in quantities equal to that released by the pre-synaptic cell, produces the same post-synaptic response as does a pre-synaptic action potential

5. Learning Objective #2 & 3 • Recall the major different categories of transmitters • Know the names of the principle neurotransmitters in the CNS (including: glutamate, GABA, acetylcholine, norepinephrine, serotonin and dopamine)

6. The keys • Small molecular weight: • Acetylcholine (ACh) • Amino acids: • Glutamate, GABA, glycine • Biogenic amines: • Catecholamines: • Dopamine, Norepinephrine (Epinephrine) • Indolamines: • Serotonin (5-HT), Histamine • Nucleotides • ATP , Adenosine

7. More keys... • Neuropeptides • Unconventional (what?) • (yes, I want to be a transmitter but I’m not going to tell you exactly how)

8. Learning Objective #4 • Compare and contrast small the synthesis and action of small molecular weight and peptide transmitters

9. Small Molecules

10. Neuropeptides

11. Back to transmission…..

12. Where are the transmitters?

13. Amino Acids • Glutamate • everywhere in CNS • major excitatory transmitter in CNS • most projection neurons in cortex use glutamate • GABA • everywhere in CNS • major inhibitory transmitter in CNS • found (not always) in local circuit neurons (interneurons) • Glycine • major inhibitory transmitter in brainstem and spinal cord

14. L-Glutamate

15. Synthesis and Degradation: GABA The GABA Shunt -ketoglutarate glutamate Kreb’s Cycle glutamic acid decarboxylase (GAD) succinic semialdehyde GABA (release & uptake) succinic acid

16. Distribution: Acetylcholine 5% Ventral horn spinal motor neurons (PNS) to skeletal muscle Brain stem motor nuclei Striatum (local) Septal nuclei to hippocampus Nucleus basalis to cortex, amygdala, thalamus PNS - autonomic Cognition - memory Motor (striatum)

17. Learning Objective #5 • Identify the brainstem nuclei associated with the biogenic amine transmitters

18. Distribution: Norepinephrine (NE) 1% Locus coeruleus to everywhere attention, alertness circadian rhythms memory formation mood

19. Distribution: serotonin (5-HT) 1% Rostral raphe nuclei to nearly all regions of the brain Caudal raphe nuclei to spinal cord mood sleep / wake cycles pain modulation

20. Distribution: Dopamine 3% Substantia nigra to striatum Ventral tegmentum to: Amygdala, nucleus Accumbens & prefrontal cortex Arcuate nucleus to median eminence of hypothalamus movement motivation sex hormones

21. H COOH + CH2-CH-NH3 HO CH2-CH-NH3 HO OH OH COOH + + HO CH2-CH-NH3 Synthesis: Dopamine (these steps occur within the cytoplasm) L-DOPA dopa decarboxylase tyrosine hydroxylase Tyrosine Dopamine

22. H + CH2-CH-NH3 HO + OH OH CH-CH2-NH3 HO OH Synthesis: Norepinephrine (these steps occur within the synaptic vesicle) Norepinephrine dopamine--hydroxylase (DBH) Dopamine

23. Transmitter termination • Clinical relevance: • Neurotransmitter transporters: • MAOs: • disease (epilepsy, ALS, Parkinson’s) • drug abuse (cocaine, amphetamine) • treatment (depression, OCD)

24. Learning Objective #6 • Compare and contrast ligand-gated and G-protein coupled receptors

25. Classes of Neurotransmitter Receptors • Ionotropic Receptors • Ligand-gated ion channels • Fast synaptic transmission (1 ms) • Are closed (impermeable to ions) in absence of transmitter • Neurotransmitter binding opens receptor (direct) • Metabotropic Receptors • G-protein coupled receptors (GPCRs) • Slow onset and longer duration of effects (100 ms & longer) • Ligand binding activates GTP-binding proteins (indirect)

26. Ligand-gated / G-protein Coupled

27. Transmitter and receptor pairing • Both ionotropic and metabotropic receptors: • glutamate • acetylcholine • GABA • 5HT (serotonin) • Just ionotropic: • glycine • Just metabotropic: • other biogenic amines (DA & NE)

28. Ligand-gated ion channels Glutamate Receptor Subunits All Other Receptor Subunits • Each subunit has multiple membrane spanning domains • Glutamate: 3 • All others: 4 • Multimers • Glutamate: 4 • All others: 5

29. Allosteric “other” binding sites

30. Congenital myasthenia • Single channel lifetime shortened • open slower & close faster (Wang et al, 1999)

31. Structure of G-protein Coupled Receptors • Single polypeptide with 7 TM domains (no subunits) • 2nd & 3rd cytoplasmic loops plus part of the intracellular tail bind to appropriate G protein

32. Agonist binding causes conformational change that activates the G-protein pertussis toxin cholera toxin

33. Direct modulation of Ca2+ channels

34. Modulation Through 2nd Messenger Pathway

35. “Retro” transmitters • NO • endocannanbinoids

36. Definitions… • Agonist = activates (opens) the receptor when it binds • Antagonist = binds to the receptor and inhibits its function • different types • Allosteric modulators = act at a site different from agonist • Desensitization = response decrease although the agonist is still present or repetitively applied • Ligand gated ion channels: • Gating = opening / closing of the channel • Kinetics = how long processes take • Affinity = tightness of the agonist binding • Efficacy = how readily the channel opens