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Inhibitory Neurotransmitters

Inhibitory Neurotransmitters. Most common in CNS are gaba ( γ-aminobutyric acid) and glycine. Glycine. Made from serine Used in spinal cord neurons at about 50% of inhibitory synapses The other 50% use gaba. Strychnine.

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Inhibitory Neurotransmitters

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  1. Inhibitory Neurotransmitters • Most common in CNS are gaba (γ-aminobutyric acid) and glycine

  2. Glycine • Made from serine • Used in spinal cord neurons at about 50% of inhibitory synapses • The other 50% use gaba

  3. Strychnine • Rat poison that blocks inhibitory neurotransmitter and cause excitation in CNS • Blocks glycine receptor that leads to membrane depolarizations and over activity and death due to seizures

  4. Gaba • Most frequently used inhibitory NT in brain & spinal cord. 1/3 of synapses use gaba • Precursors are glucose, pyruvate and glutamine • GAD= glutamic acid decarboxylase converts glutamine to gaba • Requires vitamin B6 derivative for GAD activity, so B6 deficiency can cause gaba deficiency • Noted when infant formula lacked B6=fatal seizures

  5. Re-Uptake Mechanisms • Specific Transport proteins on presynaptic membrane to reuptake intact NT • Re-uptake into glial cell • Diffusion • Degradation by enzymes and re-uptake of metabolite

  6. Gaba Removal • High affinity gaba transporters • Degradative enzymes are mitochondrial

  7. Multiple Isoforms • Each subunit can be encoded by any one of several gene or mRNA products to make 3 subtypes of receptors A and C are ionchannels, B is a metabotropic receptor • GABA receptor • 6 alpha subunit isoforms • 3 beta subunit isoforms • 2 gamma subunit isoforms

  8. The GABA a and c receptor are members of the ligand-gated channel superfamily. By analogy to the well studied nicotinic acytocholine receptors, GABAc receptors are thought to exhibit the structure shown schematically in Fig. 2. These receptors are pentomers, i.e. five subunits constitute the functional channel (Amin and Weiss, 1996). The receptors have a long extracellular domain containing ligand binding sites and several modulatory sites. In the middle of the receptor, GABA gates an ionic channel. Binding of GABA to the receptor induces a conformational change in receptor structure which leads to the opening of the channel. From webvisionmed.utah

  9. Neurotransmitter Receptors 100s NTs and 1000s or more NTRs Receptors w/o NTs

  10. Multiple Receptors for 1 NT • How are they identified & classified • How is this information used clinically?

  11. Survey of NT Receptors

  12. Figure 6-7:The neuropharmacology of cholinergic synaptic transmission

  13. Ligand • From Latin means to bind (ligare) • Any substance that binds a receptor or ion channel • Neurotransmitters • Plant & animal toxins • Chemically synthesized compound

  14. MAchR • Atropine, derived from belladona flower • Antagonizes mAChR • Ach effect on pupil of the eye is to constrict • Form of atropine is used in dilatory eye drops by opthamologists

  15. Basic Structure of NT gated ion channel • 100 nm long-barely extends the width of pm • Subunits arranged to form a barrel with interior pore through pm • All subunits have common domains named M1-M4 that are transmembrane • M1-4 form hyophobic alpha helices • Most are composed of 4-5 subunits

  16. Drugs that bind GABAa Receptors • Barbituate • Phenobarbital = anesthetic • Benzodiazapines = tranquilizers • valium • Binds GABAa subtype with gamma subunit

  17. Effect of Drugs on GABA channels • In the absence of GABA, drugs have no effect • In the presence of GABA, drugs can • Increase frequency of opening/benzodiazepines • Increase duration of opening/barbituates

  18. Pharmacology of VALIUM • Valium=benzodiazapines bind to gaba gated chloride channel • Cause the channel to stay open longer==less brain activity=calmer state of mind • Used as anti-convulsant drugs

  19. Fear and Anxiety and Gaba A modulators Anxiolytic drugs- Librium valium Edvard Munch, the scream

  20. Thebrainmcgill.ca Synapses-Gaba Anxiety Receptor By binding Benzodiazepine Back Three types Metabotropic vs ionotropic Back to anxiety NT Not the only Raphe Hormonal brain

  21. Neuromodulation Metabotropic Ion Channels Neurotransmitters bind Receptors that are not ion channels

  22. Neuromodulation • Neurotransmitter binding and ion flux are provided by two or more individual molecules. • Allows for many effects of NT on post-synaptic cell • Can regulate several channels, metabolic enzymes and gene expression • Stimulates or inhibits second messengers

  23. Effect of Second Messenger • May directly bind ion channel and regulates its opening or closing • Can activate enzyme s.a. cyclic AMP dependent PKA that phosphorylates ion channel to open or close it

  24. Effect of Symp & Parasym on Cardiac Muscle • Parasympathetic presynaptic nerve ending release Ach and slows heart rate • Sympathetic presynaptic nerve ending release NE and increase heart rate • BOTH WORK THROUGH NEUROMUDULATION USING G PROTEINS.

  25. Parasympathetic Cardiac Neuromodulation • Ach binds muscarinic Ach Receptor that inhibits cardiac muscle excitation • Ach binds receptor and the G protein alpha subunit binds a potassium channel • The K channel opens, hyperpolarizes the cardiac membrane and leads to prolonged relaxation phase of cardiac activity=slows heart rate

  26. Sympathetic Cardiac Neuromodulation • Ach binds B adrenergic Receptor that strengthen cardiac muscle contractility • NE binds B adrenergic receptor and the G protein alpha subunit activates Adenyl cyclase which produces cAMP • cAMP activates PKA which phosphorylates voltage gated calcium channel, prolonging its opening time

  27. Neuromodulation • Effects mediated by second messengers • Direct postsynaptic effects last several hundred milliseconds to hours • Secondary effects lasts days • Postsynaptic electrical responses are weak and slow

  28. Second Messengers • cAMP • cGMP • GTP • Calcium • DAG and IP3 • Arachidonic acid • May act directly or indirectly on ion channel

  29. How do G-proteins Work • Can inhibit or activate downstream molecules to increase or decrease levels of second messengers • Denoted Gs or Gi

  30. G-proteins Link Channel Activity with NT • GTP-binding protein cycles between off state (GDP bound) and on state (GTP- bound) • NT receptors catalyzes replacement of GDP with GTP. • Activated G-protein activates adenylyl cyclase that produces cAMP

  31. Short Cut Pathway • NT binds receptor that is not an ion channel but is linked to trimeric G protein • G protein becomes activated by conformational change transduced from NTR that allows G to bind GTP • Dissociates into a and bg subunit components • Gb subunit binds directly to ion channel & gates it.

  32. Long-Term Effects • Ion channel can be regulated by G-protein directly and by second messengers and enzymes s.a. PKA. • So the effect of neurotransmitter binding can have prolonged effects on ion channel activity. • An activated NT receptor can bind to many G proteins so signal is amplified • 700 types of G proteins

  33. G Protein Linked to Adenylyl Cyclase • Causes formation of cAMP and activation of PKA • PKA phosphorylates serine and threonine residues on target proteins

  34. Regulation of G protein • Some NT bind to both Gi and Gs linked receptors

  35. Neuromodulation • Allows for amplification of NT signal • Allows for long term changes in post synaptic membrane

  36. G Proteins linked to Phospholipase • Phospholipase cleaves PIP2 in the membrane • Generates to metabolic products each are second messengers • IP3 and DAG • IP3 causes calcium release from intracellular stores • DAG activate PKC

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