Summers
- Kandel, Schwartz and Jessell:
Read pages 253-277 for this lecture
acronyms
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Summers |
Neurobiology |
text: Principles of Neural Science - Kandel, Schwartz and Jessell: Read pages 253-277 for this lecture acronyms end |
XXIV. Synaptic Vesicles back to XXIII. Neuromodulators and Neuropeptides A. Most neurons contain 2 populations of vesicles 1. small = 50 nm in diameter 2. large = 70 - 200 nm 3. distinct and independent (probably) B. Transmitters/Modulators are stored in vesicles 1. rate of synthesis does not equal rate of release 2. protected from degradative enzymes a. which control cytosolic levels of small-molecule transmitters i. catabolic enzymes in terminal cytoplasm exist only for small-molecule transmitters, as peptides are only made in the soma 3. Transmitter is actively taken up into vesicles a. move along pH gradient (chemiosmotic migration) C. Vesicles release transmitter by exocytosis 1. small vesicles contain small molecule transmitter a. active zones 2. large contain amine transmitters, core proteins, and secretory peptides a. no active zones 3. not all substances are released by vesicular fusion a. prostaglandins, NO, CO D. Vesicle membranes contain proteins 1. transmitter packaging and processing a. transmitter transporter i. like reuptake transporter (1) e.g. DAT, NET, SV2 ii. \ neurons with different transmitter types have different vesicles b. Vacuolar proton pump creates electrochemical gradient 2. participate in ATPase (kinesin, dynein) mediated movement 3. facilitate vesicle crosslinking, fusion and exocytosis E. Vesicle pools: storage and delivery 1. Synapsin 1 a. crosslinks vesicles, anchors to actin i. inhibits mobilization 2. Ca++/Calmodulin-dependent kinase 2 ii. removes inhibition iii. mobilization of vesicles in storage pool to docking sites at active zones 3. caldesmin binds to actin, tubulin, and Ca++ F. Membrane Trafficking: Fusion and release 1. Synaptotagmin a. interacts with active zone proteins i. syntaxin and neurexin (1) docking and fusion ii. binds Ca++ (1) Ca++ dependent 2. Synaptobrevin (also called VAMP) a. interacts with syntaxin and SNAP-25 (1) docking and fusion 3. Rab3 (related to Ras = G protein) a. vesicle targeting and docking 4. synaptophysin is possibly a fusion pore (similar to connexin) G. Neurotransmitter release is mediated by Ca++ influx 1. voltage gated Ca++ channels (opened by presynaptic Action Potential) a. near active zones 2. Ca++ disinhibits mobilization (via calmodulin) 3. vesicular SNARE binds terminal SNARE a. SNARE (SNAP Receptor) complex is made from synaptobrevin, syntaxin, and SNAP-25 in the vesicle and terminal i. 4 helices (1 each VAMP & syntaxin, 2 from SNAP) ii. VAMP in vesicle, SNAP & syntaxin in terminal membrane iii. minimal fusion apparatus b. synaptotagmin + neurexin/syntaxin complex also docks vesicle c. fusion pore (synaptophysin) + Ca++ channels creates active zone i. pore proteins in vesicle and terminal line up ii. facilitated by docking proteins and SNARE d. binding facilitated by GTP phosphorylation of Rab3 to remove n-Sec1 from tSNARE 4. NSF (N-ethylmaleimide sensitive factor) + a-SNAP (soluble NSF attachment protein) bind, and then bind to SNARE complex 5. ATP + dissociation of NSF and a-SNAP allow fusion H. vesicle release can also be controlled by synaptic connections: regulating Cl-, Ca++ or K+ 1. presynaptic inhibition or facilitation a. e.g. GABA or glutamate (respectively) 2. presynaptic autoreceptors a. e.g. a2 adrenergic receptors I. Synaptic vesicles are recycled 1. results in recycling receptors and other membrane constituents 2. delivery of trophic factors (fast retrograde transport) 3. lysosomal degradation 4. recaptured in active zones J. Removal of transmitter terminates transmission 1. diffusion removes some 2. degradative enzymes (e.g. AChE) may be a part of the membrane 3. recapture in active zones a. high affinity transporter molecules i. reuptake receptors = membrane spanning proteins (1) require ATP (2) exchange with ions (usually Na+) (a) cotransport (3) common family of proteins for different transmitter reuptake (a) gene family K. Colocalization 1. more than one transmitter substance may be found in the vesicles of one neuron a. often an amine transmitter + a neuroactive peptide ` i. an exception: retina colocalizes ACh and GABA ii. more than one peptide may be released (1) especially from large precursor molecules (e.g. POMC) b. found both centrally and peripherally c. may act synergistically (e.g. ACh and VIP) i. cotransmission ii. the peptide may potentiate the release of the transmitter, e.g. VIP increases the release of ACh iii. effects may be similar but different in duration (1) classical transmitters may cause rapid effects with short duration (2) peptides may provide a slow, longer lasting effect d. may have presynaptic inhibitory effects e. usually the colocalized peptide has an auxiliary messenger function i. or not immediately involved in the chemical transmission process - modulation ii. differential release (1) low frequency transmission results in release of small vesicles from active zones (maybe) (2) high frequency, large from other than active zones 2. DA found with CCK or Neurotensin in the ventral mesencephalon 3. NE with Enkephalin, NPY, or AVP in the locus ceruleus 4. Epi with Neurotensin, Substance P, or NPY in the medulla 5. 5-HT with Substance P, TRH, Substance P & TRH, CCK, or Enkephalin in the Raphe 6. ACh with VIP in the cortex, and Substance P in the pons 7. GABA with Somatostatin, CCK, or NPY in the cortex, with Somatostatin in the thalamus and hippocampus, with galanin in the hypothalamus, with enkephalin or neurotensin in the retina 8. Glycine with neurotensin in the retina 9. not every neuron has more than one transmitter/modulator substance a. the hypothalamus is particularly rich in colocalization 10. many colocalizations are phylogenetically conserved 11. receptors must be present for all substances released a. receptor sites may be closely related, even coupled (e.g. 5-HT & TRH)
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