Q: Which cells produce eicosanoids? A: Almost all cells. Q: Eicosanoids act mainly as what type of hormone? A: Local hormones. Q: Eicosanoids are dreived primarliy from what acid? How many carbons is this acid? A: Arachadonic, 20-carbon polyunsaturated acid. Q: Eicosanoids participate in what processes (5)? A: Inflammatory response, smooth muscle contraction, increase water and Na+ excretion, regulate bp, serve as modulators. Q: Name 2 ways that eicosanoids serve as modulators A: Constrict or dilate vessels, bronchodialation and bronchoconstriction. Q: Are eicosanoids inactivated and excreted rapidly or slowly? A: Rapidly. Q: What is the most common source of arachidonic acid? A: membrane phospholipids. Q: Compounds that are signals for Eicosanoids production bind to the membrane and activate activate what enzyme? A: Phosholipase (A2). Q: What do phospholipases do? A: Cleave arachidonate from the membrane phosphilpids (Usually found at 2 position on glycerol). Q: What are stimuli that can activate phospholipase A2? A: Histamines ans cytokines. Q: What three enzymes convert arachidonic acid to Eicosanoids in the cytosol? A: cyclooxygenase (COX), lipooxygenase (LOX), cytochrome P450 (POX). Q: COX pathway leads to synthesis of? A: prostoglandins and thromboxanes. Q: LOX pathway leads to synthesis of ? A: leukotrines, HETEs, lipoxins. Q: POX leads to synthesis of? A: epoxides, HETEs, EETs. Q: Describe structure of prostoglandins? A: 20 carbons, internal 5-C ring; of active they contain a hydroxyl group at C-15 and a double bond between C-13 and C-14. Q: How do thromboxanes differ from prostoglandins structurally? A: 6 carbon ring and that includes an oxygen (TXA2 has Oxygen on C-9 and C-11). Q: Where are COX1 and COX2 located? A: ER. Q: Are the COX enzymes consituative or regulated? A: COX-1 is normally constituative and 2 is expressed transiently. Q: What induces COX-2 (3)? A: nitrogens, proinflamitory cytokines, liposaccharides (LPS). Q: When is COX-2 mRNA and protein greatly increased? A: During inflamation. Q: COX-1 is found in most tissues bu hughly expressed in? A: Seminal vesicles, platelets, renal collecting tubules, monocytes, gastric mucosa. Q: COX-1 and COX-2 have differences in? A: Utilization of fatty acids and susceptibility to inhibition by asprin-like drugs. Q: Which genes codes for COX3? A: COX-1, but it keeps an extra intron. Q: Where is COX-3 most abundant? A: canine cerebral cortex. Q: COX-3 is selectively inhibited by? A: Acetominophen, explains why acetominophen is analgesin but not anti-inflamitory. Q: What causes pain in the inflamitory response? A: release of chemical compounds and compression of nerves in the viscinity of inflamation. Q: Activation of comploment sysytem or blood clotting cascade causes production of what? A: Histamines from mast cells and kinins from clelavage of kininogens. Q: Histamines and kinins have what affect? A: Increase vascular permeability and stimulate syntheses of eicosanoids that act on motility and metabolism of white blood cells. Q: Do prostoglandins act on thermoregulatory centers of the brain to produce fever? A: Yes. Q: NSAIDs have what effect on prostaglandins. A: NSAIDs all reduce the formation of prostaglandins. Q: What are the unique properties of aspirin (how it funtions) A: Aspirin acetylates and irreversibly inactivates COX-1 and COX-2 Q: T or F Cyclooxygenases are inhibited by all NSAIDs? A: T Q: What are side effects of NSAIDs and what is the mechanism of casation? A: Gastroduodenal erosion (Ulcer) from inhibiting COX-1. Q: How do NSAIDs cause inflamation and analgesic activity? A: By inhibitng COX-2. Q: What is the basis and problem of the new (1999) drgs celecoxib and rogecoxib? A: They inhibit only COX-2 thus avoiding ulcers (from COX-1 inhibition). But COX-2 is in kidneys (upregulated in heart failure...) and thus they (and other NSAIDs) can cause renal problems. Q: What is thromboembolic disease and what is a preventative treatment? A: (AA-induced) platelet aggregation in the vessels. Prophylaxis (from and aspirin regimine) is acheived through decreased production of thromboxane A2. Q: Which enzyme if found in platelets and how much is made in any one day? A: COX-1 only. Platelets do not form new enzyme, and thromboxane A2 synthesis is irreversibly inhibited (from aspirin) for their 8-10 day life span. Q: What is the basis of recent data of NSAIDs prventing cancer? A: COX inhibitors are potent anti-angiogenics (vessel formation). Think about why that would help. Q: What are the 3 Mechanisms of action for prostaglandins? A: 1)Bind plasma membrane receptors 2) Transcription factor 3)Covalent modification of proteins. Q: The 2 branches of prostanoid (prostaglandin) surface receptors have what cellular action and systemic action? A: One activates A.C. = relaxing sm. muscle. the other either inhibits A.C. or stimulates PI(phosphatidiylinositol) hydrolysis =constrictin sm. muscle. Q: What are the 3 classes of lipoxygenases? Where are they found? What do they synthesize? and What do they do? A: 5,12,15 LOX, depending on what carbon t hey add oxygen to (forming hydroperoxy -OOH groups). There is tissue variability and LOX's synthsize Leukotines, H(P)ETE and Lipoxins. Q: T or F Once a LOX add an oxygen to the double bond, the double bond is completely reduced with hydrogen molecules? A: F the double bond isomerizes to a position one carbon away from the hydroperoxy group added adn transformes from cis to trans. Q: What is the page number of the Nature article explaning a novel mechanism of anti-inflamatory activity? A: 103 2000 article. This will definately be on the test. :) Q: T or F Prostaglandins and thomboxanes have a long half-life allowing longer stimulatory effects? A: F Their half-life is only seconds or minutes. They are inactivated by oxidation of the 15-hydroxy group to a ketone. Another oxidation happens on the beta and omega carbon producing dicarboxilic acid that are excreted. Q: What was his example of the nuclear transcription factor for prostaglandin action(the second mechanism of action)? A: PPAR-gamma. Peroxisome proliferator-activated receptor. a superfamily used for retinoid, steroid, and thyroid hormones. It acts directly as a transcription factor. Q: The third action of prostaglandins involves covalent modification of enzymes, what examples from a Nature article and Fitzpatrick's group at Huntsman demonstrates this? A: The protaglandiins directly inhibit a key protein kinase by modifying a cystein residue. Fitztpatrick's group showed that it inhibits a ubiquitin isopeptidase of the proteasome system Q: T or F Prostaglandin products of COX-2 ALWAYS potentiate the inflammatory response? A: F At late stages of inflammation, COX-2 direcst sythesis of anti-inflammatory prostaglandins. One way is through receptor-PPAR-gamma activity. Also the 2 examples in nature and Fitzpatrick's group. Q: The synthesis of leukotrines begins with HPETE formation. HPETE's can then be reduces to hydroxy metablites or metabolized to form lekotrienes or lipoxins. An example he used was the leukotriene LTA4. Which form of LOX is it made from, and where? A: LTA4's are made from LOX-5 and function in contracting smooth muscle (thus producing asthma). LOX-5 is concentrated in the lungs. Q: Which of the three groups of eicosonoids is thought to contribute to the pathophysiology of asthma? A: Leukotrienes Q: What are four factors that result in/ contribute to asthma? A: 1. Contraction of airway smooth muscle 2. mucosal edema 3. increased secretion of mucus, and 4. infiltration of the airway wall by inflammatory cells Q: What are the two main classes of leukotriene modulators (the first new asthma drugs in 20 years) used to treat asthma? A: 1. CysLT1 receptor antagonists 2. leukotriene synthesis inhibitors Q: What is the effect of antileukotriene drugs in asthma patients? A: They acutely bronchodilate the airways of patients with baseline bronchoconstriction. Q: What enzyme is a novel therapeutic target for vascular disease? A: 15-lipoxygenase Q: How may 15-lipoxygenase be involved in vascular disease? A: It may be involved in processes that modify native LDL such that it is avidly taken up by tissue macrophages. Q: What is the leading cause of death in the Western world? A: Atherosclerosis (heart disease). Q: In two animal model studies, what enzyme's inhibition virtually inhibited vascular lesion formation? A: The inhibition of 15-LOX. Q: What is the initial precursor molecule for lipoxin synthesis? A: Arachidonic acid. Q: What 2 enzymes act to produce lipoxins from the 20 carbon fatty acid precursor? A: 15-lipoxygenase followed by the action of 5-lipoxygenase. Q: Lipoxins promote what two activities/actions by what one type of blood cell? A: They promote (1) chemotaxis and (2) superoxide anion production in LEUKOCYTES. Q: What are the 3 products of the monoxygenases of the POX pathway? A: 1. epoxides 2. certain forms of HETEs (such as omega-hydroxy derivatives) and 3. diHETEs (diol forms). Q: The cytochrome P450 pathway is also know as...? A: The POX pathway. Q: What are three effects of POX pathway products? A: The epoxides, HETEs, and diHETEs affect 1. peptide hormone secretion 2. Vascular and bronchial smooth muscle tone 3. ion transport Q: Why can marijuana be used to treat cachexia in AIDS patients? A: Marijuana is an appetite stimulant indicated for cachexia "wasting disease" where the body atropies. Q: Cannaboids can inhibit what enzyme in what kind of cells? A: They inhibit adenylate cyclase in neuroblastoma cells. Q: Into what general class of receptor types do cannaboid receptors fall? A: They're G-protein coupled receptors (GPCRs). Q: What are the two cannaboid receptors that have been cloned to date? A: CB1 and CB2 Q: Where are CB1 receptors found? CB2 receptors? A: CB1s are found in many brain regions whereas CB2 is localized to immune system cells. Q: What is the endogenous agonist that acts on the CB1 and/or CB2 receptors? A: Anandamide. Q: Anandamide means what in India sanskrit? A: "I have a strong dislike for Biochemistry" or "Bringer of inner bliss and happiness" Q: What fatty acid is the precursor for anandamide? A: Arachidonic acid, just like the other eicosonoids. Q: Anandamide consists of what two molecules linked through an amide linkage? It is synthesized via what molecule? A: Arachidonic acid and ethanolamine. Via N-arachidonylPHOSPHATIDYLethanolamine. Q: How/why does anandamide deviate from the classical definition of a neurotransmitter? A: Due to its hydrophobicity and tendency to diffuse across membranes, it can't be stored within a synaptic vesicle. Q: What are three positive things seen in CB1 knockout mice? A: 1. Improved memory 2. Decreased appetite 3. Decreased tendency to become addicted to opiates Q: What are three negative things seen in CB1 knockout mice? A: 1. Increased sensitivity to pain 2. reduced locomotor activity and 3. shorter life spans Q: How is anandamide stored as a (non-classical) neurotransmitter? A: It is stored in a phospholipid precursor form to be released following calcium-dependent activation of appropriate enzymes or ion channels. Q: Once the phospholipid precursor form is activated how does anandamide act as an endocannabinoid? A: It travels backwards across the synaptic cleft, acting as a retrograde messenger at cannibinoid receptors that are present on nearby presynaptic axon terminals. Q: What is the estimated percent of the total risk for drug abuse and addiction that is due to genetic factors? A: 40-60%, but precise identities conferring vulnerability remain mostly unknown. Q: A homozygous (specific) mutant form of what enzyme is strongly associated with both street drug use and problem drug/alcohol use? A: Fatty acid amide hydrolase (FAAH) Q: What is the estimated percent of the total risk for drug abuse and addiction that is due to genetic factors? A: 40-60%, but precise identities conferring vulnerability remain mostly unknown. Q: A homozygous (specific) mutant form of what enzyme is strongly associated with both street drug use and problem drug/alcohol use? A: Fatty acid amide hydrolase (FAAH) Q: What type of mutation/polymorphism in FA Amide Hydrolase, when homozygous in an individual, is associated with problem drug use? A: A single nucleotide polymorphism Q: What is result of the mutation/polymorphism in FAAH that is found to be associated with street/problem drug/alcohol use? A: The FAAH variant, though possessing normal catalytic capabilities, is more sensitive to proteolytic degradation Q: What amide (besides anandamide) is another important substrate for FAAH? A: Oleamide, the amide of oleic acid Q: In what part of the body of sleep deprived rats can oleamide be found? A: In their CSF Q: What is the action of accumulated oleamide in sleep-deprived rats and mice? A: It can induce sleep in rats and mice Q: T/F Inhibition of FAAH in rats causes them sleep longer. A: True; oleamide builds up in the CSF of the animals, inducing sleep. Q: The transition to a CHRONIC pain phase involves changes in/at what three levels/sites? A: 1. spinal cord 2. brain 3. there's also remarkable modulation at where pain messages are initiated -- at the level of the primary snsry neuron. Q: Pain may be made worse, in part, from the production and release of chemical mediators from what two things/cells? A: The primary sensory terminal and from non-neural cells. Q: Components, such as lipids, can alter neuronal ________ by interacting with ___ _______ on the nociceptor surface. A: Excitability is altered by interaction with ion channels. Q: TRP channels respond to what 4 stimuli? A: 1. Temperature 2. Pain 3. Pheromones 4. Taste ... and other stimuli Q: Describe a mammalian TRP channel (transmembrane domains, tetramer vs. trimer vs. dimer)? A: They "are putative six-transmembrane polypeptide subunits that assemble as tetramers" R-7 Q: Are TRP channels permeable to anions or cations? A: Cations Q: The TRPV vanilloid receptor was identified by expression cloning using what compound as a ligand? A: Capsaicin, from hot peppers Q: What 2 conditions activate the TRPV1 channel? What two compounds inactivate the TRPV1 channel? A: 1. Heat >43C or decreased pH activate 2. PIP2 or anandamide inactivate it Q: T/F Some nociceptors can be activated by mechanical stress. A: True Q: What channel does prostaglandin E2 (PGE2) modulate? A: The TTX-insensitive sodium channel Q: What channel is a potential mechanosensory transducer in mammals (as deduced from the fact that mice lacking this are relatively insensitive to whisker movement)? A: The tetrodotoxin-insensitive brain sodium channel (EnaC). Q: What usually initiates eicosanoid synthesis? A: PLA2-mediated release of arachidonic acid from membrane phospholipids. Q: What is the common property/action of LOX, POX, and COX enzymes? A: They insert oxygen into the 20C backbone of AA Q: Binding of arachidonate derivatives to various receptors can affect what (3 listed here) processes? A: 1. Inflammatory responses (including pain) 2. Excretion of water and Na 3. Constriction of bronchioles and arteries