Receptors & Transmitters

1. Receptors & Transmitters Basic Neuroscience NBL 120 (2007)

2. locks & keys

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) • 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. 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

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

7. Small Molecules

8. Neuropeptides

9. Back to transmission…..

10. 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

11. glutamate

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

13. Distribution: Acetylcholine 5% Ventral horn spinal motoneurons (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)

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

15. Distribrution: 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

16. 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

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

18. 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

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

20. 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)

21. 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

22. Ligand-gated / G-protein Coupled

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

24. 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

25. Binding sites on GABA receptors • Opening of the channel requires GABA • The other sites are “allosteric” for GABA binding

26. Congenital myesthenia • Single channel lifetime shortened  - opening rate decreased  - closing rate increased (Wang et al, 1999)

27. Receptors  G Proteins  Effectors Effectors adenylyl cyclase phospholipase C cGMP phosphodiesterase phosphoinositol-3-kinase Ca2+ channels K+ channels Na+ channels Metabotropic Receptor G Protein aka GTP binding protein heterotrimeric G protein large G protein

28. 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

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

30. Direct modulation of Ca2+ channels

31. Modulation Through 2nd Messenger Pathway

32. “retro” transmitters • NO • endocannanbinoids