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40 Cards in this Set
- Front
- Back
Neuropeptide signaling history |
Evolutionarily old - hydra uses peptidergic signaling instead of classical and yeast communicate with peptides (alpha-mating factor) |
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Neuropeptide families |
Families are formed either from different genes (via gene duplication and divergence) or from related sequences within same gene product due to splicing. |
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Opioid peptide gene family members |
1. POMC 2. Prodynorphin 3. Proenkephalin 4. Proorphanin/FQ |
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Evolution of RF-Amide subfamilies |
Useful motif (arginine-phenylalanine) was useful. Gene duplication lead to different precursors with C terminus RF with other sequences that bind to receptors. Involved in various functions including signaling, pain, reproduction. |
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Neuropeptide size |
Less than 10 kD |
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Neuropeptide and convential transmitter relationship |
Both are found at majority of CNS synapses. Can be in same vesicle or different ones. Peptides can modulate conventional signaling |
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LHRH modulation of ACh activity |
ACh has rapid action and does not diffuse far because rapidly broken down and removed. LHRH diffuses further than ACh and acts on receptors at more distanct postsynaptic terminals - influences activity at many terminals. |
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Strength of neuronal activity and type of vesicle released |
Single pulse releases small vesicles with classical transmitter High frequency pulse releases large dense core vesicles with peptide neurotransmitters (and some classical neurotransmitters). |
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Endogenous opioid peptides |
Discovered using assay of ileum in water bath. Shortens when electrically stimulated.
Apply fractionated spleen extract - inhibits electrically stimulated contraction. Found Met-enkephalin and Leu-enkephalin, which have same sequence except terminal C terminus amino acid. |
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Radioreceptor assay |
Also used to discover endogenous opioid peptides. Stereo-specific assay Radiolabel drug and bind to brain membranes. Add fractionated brain extracts and follow fractions able to displace radioactive stereoisomer from membrane (eliminate non-specific binding). |
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Correlation between guinea pig ileum contraction assay and radioreceptor affinity assay |
Perfect correlation Both are measuring opioid receptor |
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Opioid peptides |
Beta-endorphin Met-enkephalin Leu-enkephalin Dynorphin (extended leu-enkephalin) alpha-neo-endorphin Share common Tyr-Gly-Gly sequence (business end) and other end which directs peptide to specific receptors. |
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Structure of "business end" of opioid peptides |
Resembles morphine in space filling model Explains why humans have receptor for plant compounds |
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Endorphin |
Entire class of endogenous morphines including enkephalins |
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Enkephalin precursors |
Preproenkephalin B arose from duplication of preproenkephalin A. Preproenkephalin A has 4 met-enkephalins and two extended enkephalins (Arg-Gly-Leu, Arg-Phe) Preproenkephalin has two Leu-enkephalins. All are bounded by basic pairs. |
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Precursor of beta-endorphin |
C-terminus of POMC Betaendorphin starts with Tyr-gly-gly but no paired basic after Tyr-gly-gly-phe-met so not processed to met-enkephalin But active in opioid receptors because tyrosine is liberated (free tyrosine = opioid activity) |
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Brain distributions of beta endorphin and enkephalin |
Majority of endorphins are in hypothalamus and pituitary Majority of enkephalins are in inner neurons of striatum But, opioid systems are present in many nuclei and in dopaminergic system. |
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Neuropeptide trafficking |
Begins in cell body. Secreted protein goes through ER, through golgi stacks. Packaged into vesicles at trans-Golgi and then shuttled to terminal. Takes long time to synthesize and reach docked stage |
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Regulation of neuropeptide expression |
Transcriptional Activity at synapse sends signal to cell body. Transcription factors such as CREB are phosphorylated to add additional precursors or enzymes. |
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Regulated secretory pathway of neuropeptides |
Few post-translational modifications. Commonly amidated in trans-golgi. Cleaved at trans-golgi and granules by prohormone convertases 1/3 and 2. These enzymes are not present in organs that do not do neuropeptide signaling (e.g. liver). |
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Neuropeptide precursor maturation |
Pairs of basic residues between final neuropeptides are cleaved. Carboxypeptidases get rid of overhanging bases at C terminus. In half of neuropeptides, glycine of pair of bases is turned by amidating enzyme into an amide group that provides stability and may engage in signaling. |
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Can a neuropeptide precursor generate peptides acting at different places? |
Yes POMC generates ACTH (adrenal medulla) and beta-endorphin (opioid receptors). |
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Tissue-specific processing of POMC |
In anterior pituirary, PC1/3 are only present to make ACTH In intermediate pituitary, PC2 is present which is not as specific as PC1/3. Cleaves ACTH into alpha MSH. Beta-endorphin can be acetylated to remove exposed tyrosine, inactivating. |
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Neuropeptide GPCRs |
Big peptides bind to extracellular N terminus |
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Opioid receptor analogousness |
Mu, kappa, delta Mostly same in transmembrane areas Different in G protein coupled C terminus and ligand binding N terminus |
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Correlation between enkephalin and opiate receptors |
Opiate receptors are present where enkephalin is present. Lack of correspondence between mRNA and opiate receptors because mRNA is located in cell body, not nerve terminal. |
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Ligands for opioid rceptors |
Mu - binds mostly beta-endorphins Delta - binds mostly met-enkephalins Kappa - binds mostly dynorphins Each can also bind other opioids. All are GPCRs, linked to inhibition of adenylate cyclase. Each has subtypes as well. |
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Opioid precursor processing and receptor affinity |
If process into larger peptides (PC1/3 generated), work on mu receptor. If smaller peptides (PC2 generated), work on delta opioid receptor. |
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Opioid receptor function |
Mu reeceptors - analgesia, respiratory effects Delta receptors - analgesia in spinal cord Kappa receptors - analgesia in spincal cord and psychoactive effects |
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Ways to generate diversity in neuropeptide action |
1) Genetic - from various families 2) Splicing variants - transcriptional 3) Processing variants - differential processing 4) Receptor variants and heterodimers 5) Receptor modulators |
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Tracts that mediate pain transmission |
Spinoreticular tract - conveys information from medulla to mid brain to cortex. Spinomesenphalic tract - similar pathway but terminates in periaqueductal grey. |
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Ascending pain pathway |
Afferents with cell bodies in DRG release excitatory neurotransmitters - substance P, CGRP, and glutamate Enkephalin on interneurons inhibit release of neurotransmitter. |
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Cone snail toxins |
Blocks flow of Ca2+ required for fusion of vesicles and transmission of pain information. Blocks pain transmission to higher center through tracts. |
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Presynaptic inhibition of signaling by opioid peptides |
Interneuron releases enkephalins which binds to opioid receptors to modulate release of excitatory neurotransmitter i.e. substance P |
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Imaging changes in patients with central neuropathic pain |
Observe reduced binding of radioactive substance in thalamic and cortical areas - opiate signaling is reduced. |
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Levels of substance P and cGRP in arthritis |
Treat animal with experimental arthritis. Stain dorsal horn for excitatory neurotransmitter. Glutamate, Substance P, and cGRP is increased compared to control. |
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Migraine therapeutic |
Inject antibodies against cGRP to nerves in subarachnoid space to relieve migraines Peptides haven't been successful because those that relieve pain are addictive. |
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Enkephalinases |
Neuropeptidases in synaptic cleft are cleaved by exopeptidases (neprilysin, aminopeptidase N) |
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DENK inhibitors |
Dual enkiphalase inhibitors Block action of neprilysin and aminopeptidase, increase concentration of enkephalins so it inhibits substance P. Treat intractable pain. |
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Difference between classical and peptide transmitters |
Much lower concentrations released of peptide transmitters Peptides synthesized in cell body and released from large dense-core vsicles. Peptides act slower Never reuptaked and reused. Always GPCR receptor. |