This preview has intentionally blurred sections. Sign up to view the full version.View Full Document
Unformatted text preview: 1 Lecture 5: Neuropeptides and Hormones Lecture 5: Objectives-Neuropeptides • Define “peptide” and contrast with “neuropeptide” • Compare and contrast the synthesis, storage and release of neuropeptides with those of the classical neurotransmitters (e.g., dopamine or serotonin; will see next lecture) • Describe how N terminal acetylation and C-terminal modifications can affect the activity of the neuropeptide • Describe the difficulties faced by neuropeptide pharmacologists regarding the design of selective agonists and antagonists for neuropeptide receptors • Discriminate between opiates and opioids • Compare and contrast the three main classes of opioid peptides in terms of their precursors, and receptor preferences • Describe the major intracellular signaling pathway used by opioid receptors • Describe the mechanisms of action of morphine, heroin, oxycodone, codeine, naloxone and naltrexone and explain how these drugs impact addiction by affecting dopamine transmission within the nucleus accumbens • Explain how by affecting dopamine release in the nucleus accumbens, kappa agonists might lead to dysphoria Peptide Neurotransmitters or Neuropeptides-small proteins, made up of the 20 amino acids; joined by peptide bonds-neuropeptide: peptides that serve as neurotransmitters; can also serve as hormones 2 Neuropepetide Synthesis 1: neuropeptides are encoded by genes; “ propeptides ”; regulated like any other protein in the body 2: Pro-peptide RNA translocates to the ER, guided by a “ signal peptide ” 3: signal peptidase cleaves bond between the propeptide and signal peptide propeptide 4: Propeptide is released from the ribosome and undergoes extensive posttranslation modification to become the active neuropeptide (cleavages and modifications at specific amino acid residues) Processing of POMC (proopiomelanocortin) 1: The POMC gene encodes the propeptides for a number of active neuropeptides incl. ACTH, - endorphin and melanocyte- stimulating hormone or MSH ( prepropeptide ) 2: The prepropeptide is translocated to the ER where it is translated into propeptides 3. The propeptides are processed by prohormone convertases 1 and 2 (PC1 and PC2); step-wise reaction, cleaving certain dibasic residues (e.g., Lys-Arg; Lys-Lys, Arg-Arg & Arg-Lys) smaller peptides with Lys and Arg at their N- and C-termini 4. carboxypeptidase E (CPE) and aminopeptidase remove these basic residues 1 2 3 Processing of POMC (proopiomelanocortin) 5: N-terminal acetylation via N- acetyltransferases can occur which regulates the activity of the neuropeptide-the effect of acetylation depends upon the particular peptide being processed: a) -MSH activity is increased by N-terminal acetylation b) endorphin activity is decreased by N- terminal acetylation 6: Amidation of glycine on C- terminus can occur via PAM NOTE: the specific neuropeptides synthesized from a prepropeptide gene depend upon the tissue because different tissues contain different prohormone convertases or CPE 3...
View Full Document
- Spring '11