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Topic 2d Neurotransmission

Topic 2d Neurotransmission. Jan 2014. Transmission of Signal Strength at Synapse. Response of postsynaptic cell influenced by amount of neurotransmitter in synapse and number of receptors. Signal Transmission at a Chemical Synapse. Figure 4.16. Neurotransmitters.

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Topic 2d Neurotransmission

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  1. Topic 2dNeurotransmission Jan 2014

  2. Transmission of Signal Strength at Synapse • Response of postsynaptic cell influenced by amount of neurotransmitter in synapse and number of receptors

  3. Signal Transmission at a Chemical Synapse Figure 4.16

  4. Neurotransmitters • More than 50 known substances • Categories • Amino acids • Neuropeptides • Biogenic amines • Acetylcholine • Miscellaneous (gases, purines, etc.) • A single neuron can produce and release more than one neurotransmitter

  5. Dale’s Principles • Candidate NT must be present in the presynaptic terminal • Candidate NT must be released, upon presynaptic stimulus, in amounts sufficient to effect a response in the postsynaptic cell • When added to extracellular fluid, the candidate NT should induce the same changes as the endogenous NT • A mechanism for removal should exist • Effects of drugs on transmission at the synapse must be similar for both endogenous and exogenous NT

  6. Neurotransmitters • Can be excitatory or inhibitory • Most prevalent NT is glutamate • Usually excitatory • GABA (γ-aminobutyric acid) • Usually inhibitory

  7. Table 4.4

  8. Agonists/Antagonists http://www.health.bcu.ac.uk/physiology/agonists.gif

  9. Neurotransmitter Action • Inhibitory neurotransmitters • Cause hyperpolarization of membrane • Inhibitory postsynaptic potential (IPSP) • Make postsynaptic cell less likely to generate an AP • Excitatory neurotransmitters • Cause depolarization of membrane • Excitatory postsynaptic potential (EPSP) • Make postsynaptic cell more likely to generate an AP

  10. Glutamate • Used at most fast excitatory synapses in brain and spinal cord • Used at “modifiable” synapses • important in memory and learning

  11. GABA • Used at majority of fast inhibitory synapses in the brain • Many sedatives enhance GABA effects • Glycine has a similar role in the spinal cord

  12. Dopamine • Important in “reward” neural circuits • Dysfunctional in Parkinson’s Disease and schizoprenia

  13. Serotonin • Monoamine NT • ~90% is produced in the intestine; remainder in CNS • Regulates sleep, appetite, memory and learning, etc.

  14. Inactivation of NTs • 4 different mechanisms • Diffusion • Enzymatic cleavage • Uptake by astrocytes • Uptake by presynaptic terminal

  15. Postsynaptic receptors • 2 types • Ionotropic • Directly opens ion channels • Metabotropic • Works indirectly via metabolic changes to the postsynaptic cell to open ion channels

  16. Ionotropic Receptor Function Figure 4.28a

  17. Ionotropic Receptors • Act as ligand-gated ion channels • Some can conduct multiple ions • i.e. Nicotinic Acetylcholine (ACh) receptor • Glutamate AMPA receptor • Equally permeable to K+ and Na+

  18. Fast & Slow Synapses • Until 1980s • Was thought that all synapses were fast • Direct activation of ion channels • Then researchers found: • 2nd messenger mediated cell signalling systems • Slower synaptic actions • norepinephrine

  19. Metabotropic Receptor Figure 4.28b

  20. http://www.arts.uwaterloo.ca/~bfleming/psych261/lec4se2.jpg

  21. Receptors for Acetylcholine • Cholinergic receptors • Nicotinic receptor • Ionotropic • Muscarinic receptor • Metabotropic • Linked to ion channel function via G-protein

  22. Receptors for Acetylcholine Figure 4.29

  23. Nicotinic Receptor http://www.nature.com/nrn/journal/v3/n2/images/nrn731-f1.gif

  24. Muscarinic Receptor http://www.ncbi.nlm.nih.gov/books/NBK28014/bin/ch11f10.jpg

  25. Receptors for Acetylcholine Table 4.5

  26. Glutamate Receptors • 3 types • Kainate • AMPA • NMDA

  27. Glutamate AMPA Receptor http://www.chrisparsons.de/Chris/images/AMPA.jpg

  28. Glutamate NMDA Receptor http://www.frca.co.uk/images/NMDA.jpg

  29. Metabotropic Glutamate Receptor http://www.nature.com/embor/journal/v4/n3/images/embor777-f1.gif

  30. EPSPs and IPSPs • Excitatory/Inhibitory Postsynaptic Potentials • Excitatory • Production of a graded depolarization • Brief rising phase and exponential decay • Excitatory synapse usually produces a very small EPSP (<0.5 mV) • Inhibitory • Production of a brief hyperpolarization

  31. EPSPs • Excitatory—depolarization • Na+ and K+ permeability increases at the same time • No action potential • Permeability changes are voltage-independent

  32. EPSPs

  33. IPSPs • GABA • Binds to GABA receptor • Opens Cl- channels • “locks” the membrane at a value more hyperpolarized than the threshold

  34. IPSPs

  35. Second Messenger Systems • G protein coupled receptors (GPCRs) • G protein • Cyclic AMP pathway • DAG & IP3 pathway

  36. http://www.colorado.edu/intphys/Class/IPHY3430-200/image/08-23.jpghttp://www.colorado.edu/intphys/Class/IPHY3430-200/image/08-23.jpg

  37. http://www.arts.uwaterloo.ca/~bfleming/psych261/lec4se2.jpg

  38. GPCR structure • Single polypeptide • Main function—activation of G protein • 7 transmembrane domains • Ligands bind near extracellular domain • Several cytoplasmic domains near TM5, TM6, TM7 and maybe TM4 mediate G protein binding • Large protein superfamily

  39. GPCR out 1 2 3 4 5 6 7 In G G protein binding site The G protein binding site is composed of amino acid residues on the C-terminal tail and the intracellular loop between segments 3 and 4, and segments 5 and 6.

  40. G Protein Families http://isoft.postech.ac.kr/Research/POSBIOTM/image/GPCR/table_gpcr1.jpg

  41. http://www.nature.com/scitable/content/ne0000/ne0000/ne0000/ne0000/14707107/U4CP2-2_ActivatedGPCR_ksm.jpghttp://www.nature.com/scitable/content/ne0000/ne0000/ne0000/ne0000/14707107/U4CP2-2_ActivatedGPCR_ksm.jpg

  42. Activated G Protein • Can activate ion channels • Activate 2nd messenger cascades • Cyclic AMP • Phospholipase C pathway

  43. Inactivation of G protein • α subunit of G protein contains a GTPase • GTP degraded to GDP • α subunit reassociates with β and γ subunits

  44. Activation of muscarinic receptors • Cholinergic synapses in cardiac tissue • GPCR activates G protein • α subunit + GTP dissociates • β and γ subunits diffuse through membrane to activate K+ channels—causing IPSPs

  45. Cyclic AMP cascade • G protein activates adenylyl cyclase • Catalyzes conversion of ATP to cyclic AMP • Cyclic AMP activates protein kinases • Protein kinases phosphorylate other proteins • Activation of ion channels • Metabolic changes • Changes in transcription factors http://t3.gstatic.com/images?q=tbn:ANd9GcQev_GY0IC6y5BsuY4GoQ-8UaWogpktHlZpStl29YimNMDMXGP7

  46. http://employees.csbsju.edu/hjakubowski/classes/ch331/signaltrans/camp.gifhttp://employees.csbsju.edu/hjakubowski/classes/ch331/signaltrans/camp.gif

  47. cAMP pathway

  48. Cyclic AMP http://psychology.jrank.org/article_images/psychology.jrank.org/neurotransmitters-and-neuromodulators.9.jpg

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