1. Psych 181: Dr. Anagnostaras Lecture 5 Synaptic Transmission

3. Introduction to synaptic transmission Synapses (Gk., to clasp or join) Site of action of most psychoactive drugs 6.5

4. Synapses Know basic terminology: Soma Soma Axon Axon Dendrite Dendrite Synaptic vesicles Synaptic vesicles Synaptic cleft Synaptic cleft Postsynaptic Postsynaptic Presynaptic Presynaptic Glia Glia 6.2

5. Synapses Dendrites & spines 3.10

6. Synapses Types of cell-cell junctions Tight junctions membranes fused membranes fused Gap junctions close juxtaposition (2-4 nm) close juxtaposition (2-4 nm) electrical synapse electrical synapse Chemical synapses synaptic cleft (20-30 nm) synaptic cleft (20-30 nm) polarized polarized

7. Multiple types of synapses Vesicle varieties 6.4 6.3 + -

8. Multiple types of synapses Multiple patterns of connectivity Axodendritic Axodendritic Dendrodendritic Dendrodendritic Axoaxonic Axoaxonic Axosomatic Axosomatic etc. etc. 6.1

9. Steps in synaptic transmission Synthesis Synthesis Transport Transport Storage Storage Release Release Inactivation Inactivation

10. Release Excitation-secretion coupling Depolarization Depolarization Open voltage-gated Ca ++ channels Open voltage-gated Ca ++ channels Ca ++ influx Ca ++ influx Bind to Ca ++ -calmodulin protein kinase Bind to Ca ++ -calmodulin protein kinase Phosphorylation of synapsin I Phosphorylation of synapsin I Movement of vesicles to release site Movement of vesicles to release site Exocytosis Exocytosis Diffusion Diffusion

11. Exocytosis 6.17

12. Inactivation Reuptake transporters transporters Enzymatic degradation metabolism metabolism excretion excretion cycling cycling 8.13

13. Sample question In which of the following are the events listed in the correct temporal order (i.e., the temporal order associated with excitation-secretion coupling)? (a) Depolarization > calcium influx > phosphorylation of synapsin > activation of calcium-calmodulin protein kinase > exocytosis (b) Depolarization > calcium influx > activation of calcium-calmodulin protein kinase > phosphorylation of synapsin > reuptake > exocytosis (c) Exocytosis > phosphorylation of synapsin > calcium influx > activation of calcium-calmodulin protein kinase > depolarization > calcium influx (d) Enzymatic degradation > exocytosis > activation of calcium- calmodulin protein kinase > phosphorylation of synapsin > calcium influx > depolarization (e) Depolarization > calcium influx > activation of calcium-calmodulin protein kinase > phosphorylation of synapsin > exocytosis > enzymatic degradation

14. Neurotransmitters Two major types: “Classical” small water soluble molecules with amine small water soluble molecules with amine formed from dietary precursors formed from dietary precursorsNeuropeptides protein synthesis protein synthesis

15. Neurotransmitters Phenylethylamines DA, NE, E, tyramine, etc. DA, NE, E, tyramine, etc.Indoleamines 5-HT, tryptamine, melatonin, etc. 5-HT, tryptamine, melatonin, etc.Cholinergics Amino acids GABA, glutamate, etc. Neuropeptides Enkephalins, substance P, neurotensin, etc. Enkephalins, substance P, neurotensin, etc. Nonpeptide hormones

16. Receptors 6.5

17. Receptors Classification By Location Postsynaptic Postsynaptic DA GABA ACH

18. Receptors Classification By Location Postsynaptic Postsynaptic Autoreceptors Autoreceptors DA GABA ACH

19. Autoreceptors Presynaptic Presynaptic Somatodendritic Somatodendritic Terminal Terminal Release-modulating Release-modulating Synthesis-modulating Synthesis-modulating Impulse-modulating Impulse-modulating DA GABA ACH

20. Receptors Classification: By Transduction Mechanism Drug, transmitter or hormone Receptor Effector Membrane Transduction Outside cell Inside cell

21. Receptor Superfamilies 1. Ligand-gated channels binding site coupled to ion channel binding site coupled to ion channel transmitter (or drug) gates the channel transmitter (or drug) gates the channel ionotropic receptors ionotropic receptors

22. Receptor Superfamilies 1. Ligand-gated channels 2. G protein-coupled receptor coupled to G protein receptor coupled to G protein G protein activates effector G protein activates effector metabotropic receptors metabotropic receptors

23. Ligand-gated channels Ligand opens channel Ligand opens channel Ions flow down conc. gradient Ions flow down conc. gradient Rapid Rapid Rapidly reversible Rapidly reversible 5.9

24. Ligand-gated channels Examples: Nicotinic acetylcholine receptor coupled to sodium channel coupled to sodium channel drugs: nicotine, curare drugs: nicotine, curare GABA A receptor coupled to chloride channel coupled to chloride channel drugs: sedative- hypnotics drugs: sedative- hypnotics

25. G protein-coupled receptors

26. Large family all with 7 membrane- spanning regions Large family all with 7 membrane- spanning regions Receptor coupled to G protein, and G protein stimulates effector Receptor coupled to G protein, and G protein stimulates effector Slower than ion-coupled Slower than ion-coupled 6.22

27. G protein-coupled receptors Two classes: G protein directly coupled to ion channel effector is ion channel effector is ion channel G protein coupled to 2nd messenger system effector is enzyme that promotes formation of intracellular “second messenger” effector is enzyme that promotes formation of intracellular “second messenger”

28. G protein-coupled receptors Examples: Cholinergic muscarinic Cholinergic muscarinic GABA B GABA B 5-HT 5-HT Opioid Opioid Dopamine Dopamine Norepin- ephrine Norepin- ephrine

29. Second messengers Are many: Calcium Calcium cGMP cGMP Phosphoinositides (IP 3, diacylglycerol) Phosphoinositides (IP 3, diacylglycerol) cAMP cAMP cAMP (cyclic adenosine 3,5- monophosphate) cAMP (cyclic adenosine 3,5- monophosphate)

30. cAMP 6.22 1 2 3 4 5 6 7 8 9

31. Protein phosphorylation Changes structure/function of protein Consequence depends on function of protein ion channel proteins ion channel proteins enzymes enzymes cytoskeletal proteins cytoskeletal proteins vesicular proteins vesicular proteins receptors receptors gene regulatory proteins gene regulatory proteins

32. Second messengers and protein kinases have many targets from P. Greengard, Science, 2001

34. Gene regulation Second messengers can alter gene regulation: Activate transcription factors Activate transcription factors Regulate transcription Regulate transcription enhance or supress enhance or supress If enhance - new gene products If enhance - new gene products

35. Gene regulation Two phases of gene activation: Initial phase induction of immediate-early genes (IEGs) (e.g., cfos, c-jun, zif-268, etc.) induction of immediate-early genes (IEGs) (e.g., cfos, c-jun, zif-268, etc.) protein products initiate 2nd phase protein products initiate 2nd phase Second phase induction of “late-onset genes” induction of “late-onset genes” products that alter cellular function products that alter cellular function

36. Gene regulation by cAMP R= regulatory subunit C= catalytic subunit Transcription factor: CREB (cAMP response element binding protein) CREB stimulates gene transcription (eg., IEGs) 6.34

37. Convergence on CREB 6.35 Multiple signalling pathways can alter gene transcription via same transcriptionfactor 2nd messengers kinases

38. Summary 6.37 Drugs of abuse are very effective in inducing IRGs 6.37

39. Home Saline Novel Amphetamine c-fos mRNA Expression

40. Sites of drug action 6.2

41. Sample question Which of the following classes of drug action would have in common the effect of increasing synaptic transmission? (a) facilitation of release; block reuptake; inhibition of synthesis (b) blockade of the release modulating autoreceptor; facilitation of release; receptor agonist (c) receptor agonist; receptor antagonist; synthesis inhibition (d) reuptake blocker; facilitation of release; receptor antagonist (e) blocks metabolism; block reuptake; inhibits synthesis