PBL(1L) Biochemistry

Biochemistry - Chapter 26 Control of balance between substrate need and substrate availability is known as? Three ways that intertissue integration for metabolic homeostasis is achieved?

Determines whether skeletal muscle will use fatty acids or glucose as fuel Two major hormones that regulate fuel storage and mobilization? Major anabolic hormone of the body? Promotes storage of fuels and utilization of fuels for growth? Major hormone of fuel mobilization? Minimum amount of glucose required a day for an adult? Cutoff for absolute minimum amount of blood glucose before hypoglycemic episodes? Overall process of glucose flux through the BBB -> into interstital -> neuronal cells is ____ at low blood glucose levels? Effects that would occur if even a day's worth of glucose, AA, and FA's could not enter cells normally?

Hormone that acts to inhibit fuel mobilization? Nonenzymatic glycosylation slows protein __________? Action of Insulin in Adipose Tissue? Action of Insulin Skeletal Muscle? Action of Insulin in the Liver? Action of Glucagon in Adipose Tissue? Action of Glucagon in Skeletal Muscle? Action of Glucagon in the Liver? After high glucose meal, a graph of insulin release will show what? What tissue lacks glucagon receptors? When do the highest levels of insulin occur? Action of E, NE, and cortisol on metabolic homeostasis? Release of cortisol, E, and NE are controlled by what? Release of Insulin and Glucagon controlled by what? Action of E on Muscle and Liver? Action of E on Adipose Tissue? Action of Cortisol on Muscle? Action of Coritsol on Adipose? Action of Cortisol on Liver? Which counter regulatory hormone is released for fuel mobilization during periods of ACUTE stress? Which counter regulatory hormone is released for fuel mobilization during LASTING periods of stress? What stimulates the adrenal medulla to release Cortisol and E? What stimulates the release of NE? What stimulates the release of Glucagon from the α-cells of the pancrease? Message conveyed by the release of insulin to the body? An Insulinoma is what? Production of excessive insulin would result in? Glucagon and Insulin are secreted by the endocrine pancreas directly into what vessel?

Metabolic Homeostasis 1. Concentration of nutrients affects rate at with used/stored 2. Hormones carry messages about supply and demand 3. CNS uses neuronal signals to control tissue metabolism Concentration of FA Insulin and Glucagon Insulin Insulin Glucagon 190 g (150 for brain, 40 for other tissues) 60 mg/dL Slow 1. Glucose and AA would be in hyperosmolar concentrations in the blood -> severe neurological problems 2. Glucose and AA [] could rise above renal threshold, can't completely resorb metabolites -> spill into urine 3. Nonenzymatic Glycosylation of proteins -> alter tissue function 4. TAGs and VLDL would rise -> increased risk of athlerosclerotic plaque build up Insulin Degradation Promotes Glucose -> FA and FA -> TAGs (inhibits TAGs -> FA) Promotes AA -> Proteins and Glucose -> Glycogen and CO2 Promotes Glucose converstion to Glycogen and FA; also promotes AA -> Proteins (inhibits catabolism and gluconeogenesis) Promotes TAGs -> FA (for fuel) and subsequent FA release from Tissues No Effect Promotes Glycogen -> Glucose, AA -> Glucose (Gluconeogenesis), and Glucose release from Liver (inhibits storage of glucose) Insulin Spike and Glucagon Fall Skeletal muscle Approx. 30-45 minutes after a meal oppose the actions of insulin by mobilizing fats Neuronal signals direct response to changing levels of fuels in the blood Stimulates glucose production from glycogen Stimulates FA release from Adipose Tissue Catabolism of Muscle protein for AA release Stimulates FA release from Adipose Tissue Stimulates usage of AA for gluconeogenesis Epinephrine Cortisol ACTH (from Anterior Pituitary) ANS Low Blood Glucose and ANS (minor role in the release of glucagon) Glucose is plentiful and available for use as fuel or storage A tumor that produces excessive insulin Reduced blood glucose levels due to uptake into tissues Hepatic Portal Vein (via the pancreatic veins)

Insulin is a polypeptide hormone composed of how many chains? How many disulfide bonds are in the active form of insulin? Insulin is synthesized as a prehormone that is converted to proinsulin in what organelle? Disulfide bonds are formed between what two AA? Where does a protease cleave the C-Peptide from proinsulin -> active insulin? What else is transported in these vesicles? Glucose enters the β-cell through what glucose transporter? Glucose is phosphorylated to form what? G6P is then ________ through glycolysis -> TCA -> oxidative phosphorylation These reactions result in what within the β-cell? As β-cell ATP/ADP ratio increases, what happens the K+ channel? Closing of the channel leads to what? Depolarization of the membrane activates what? Ca2+ rushes in, and stimulates what? As insulin is secreted, what occurs at the same time? AA can stimulate insulin secretion, although the amount of insulin released during high protien meal is what? Examples of Gut hormones that can also trigger insulin release? Preproglucagon is produced where? Where it preproglucagon converted to proglucagon? Glucagon is rapidly metabolized, where? Plasma half-life of glucagon? Increasing levels of insulin and glucose, will inhibit what? Direction of blood flow in the pancreas carries insulin to where? What is a major positive regulator of glucagon release? Other minor positive regulators of glucagon release include? In a normal individual, as blood glucose levels drop, what else happens? High protein meal would cause what to happen to insulin and glucagon release? Type 1 diabetes is caused by what? Susceptability for Type 1 diabetes, conferred how? MODY type 2 is due to what type of mutation? MODY patients can release insulin only at what glucose levels? Therefore, MODY patients are usually always in what state? Neonatal diabetes is an inherited disorder in which newborns develop diabetes, when? What mutation results in neonatal diabetes? What kind of mutation is KCNJ11? This mutation does what to the K+ channel? Mutation of the SUR1 gene would make what difficult? What can one use to determine the rate of insulin secretion in a patient with a insulinoma? Can you use this measurement for diabetes mellitus patients as well? Patients with Type 1 diabetes have increased/decreased levels of insulin in their blood? Patients with Type 2 diabetes have what level of insulin in their blood? Insulin Mechanism for Receptor Binding? Five basic tissue-specific reponses to insulin:

Two 3, two interchain and 1 intrachain (A-chain) rER Cysteine residues In the storage vesicles secreted by the Golgi Zinc GLUT2 G6P metabolized Increased ATP It is inhibited Membrane Depolarization Ca2+ channel Fusion of the insulin-containing transport vesicles with the PM Synthesis of new insulin Less than the amount released during a high carb meal GLP-1 and GIP (released after ingestion of food) In the rER Lumen of the ER Liver and Kidneys 3-5 minutes Release of glucagon α-cells (they are downstream from the β-cells) Amino Acids Catecholamines insulin levels drop Insulin would rise (not as much as after carbo meal) and glucagon would show great increase (well above fasting) Antibody mediated destruction of β-cells genetic defect in the gene that codes for MHC II (self recognition) glucokinase mutation that results in an ezyme with a elevated Km (lower affinity for glucose - less efficient) higher than normal Hyperglycemic State Within the first 3 months of life KCNJ11 gene mutation Activating mutation for the K+ channel keeps it open, and less susceptable to the ATP inhibition -> no Ca2+ channel activation -> no insulin secretion Make it difficult to close the K+ channel -> display neonatal diabetes C-peptide, it is not cleared from the blood as rapidly as insulin Yes, because exogenous insulin does not contain C-peptide Decreased, or barely existant Normal or elevated, but it is not enough to combat the hyperglycemia Insulin binds to α subunit -> β spans the membrane -> TK phophorylates tyrosine residues on β (autoP) -> IRS1 phosphorylated -> IRS-1 binds to SH2 domains 1. Reverse glucagon stim. Phosphorylation 2. PO4 cascade that phosphorylates many enzymes 3. Induces represses/induces synthesis of specific enzymes 4. Insulin acts as a GF and has a general stimulatory effect on protein synth

Mechanism for Glucagon reaction when bound to receptor?

In the absense of glucagon bound to the receptor, what happens? Only what can keep the adenylate cyclase active? What tissue has NO glucagon receptors? What degrades cAMP? What inhibits phosphodiesterase? Any steroid hormones (cortisol) involve direct binding of the hormone where? Chronic stress of sepsis results in what? Cortisol and Glucagon all increase the rate of gene transcriptio for enzymes in what pathway? With regards to NE and E, which receptors work through the adenylate cyclase-cAMP system? What do they activate? β1 acts where? β1 majorly stimulated by? Activation of β1 receptor does what? β2 acts where? β2 also mediates what? Which is more potent agonist for the β2 receptor, NE or E? β3 is found primarily where? Activation of the β3 stimulates what? Agonists for this receptor may prove to be beneficial for what? β1 are postsynaptic receptors, mediate vascular and smooth muscle contraction, and work through what system? One of the important cellular responses to insulin is what? Mechanisms for this include:

Insulin causes __________ of of the synthesis of enzymes that are induced by glucagon Key enzyme in the gluconeogenic pathway? Phosphoenolpyruvate Carboxykinase is increased by what? Phosphoenolpyruvate Carboxykinase is decreased by what? Antagonism is exerted through

5. insulin stimulates glucose and AA transport into cells Glucagon binds to G-Protein -> Activates Adenylate Cyclase -> increase cAMP -> Activates PKA PKA -> changes the activity of enzymes via phosphorylation of them @ specific serine residues -> activates enzymes/inhibits others PKA -> phosphylates CREB -> initiates transcription Gs-protein complex binds GDP but can't bind unoccupied receptor or Adenylate cyclase continued occupancy of glucagon receptor Skeletal muscle Membrane-bound phosphodiesterase Methylxanthines, class of compounds that includes caffeine in the nucleus, where it interacts with chromatin varying degrees of glucose intolerance, if high levels of E and cortisol are present Glucose synthesis from AA (gluconeogenesis) β1, β2, β3 Gs Protein -> adenylate cyclase -> cAMP -> PKA Human Heart NE Increases rate of muscle contraction due to PKA-mediated phosphorylation of phospholamban Liver, Sk. M and other tissues involved in fuel mobilization vascular, bronchial, and uterine smooth muscle contraction Epinephrine Adipose tissue FA oxidation and thermogenesis weight-loss Phosphatidylinositol bisphosphate system via activation of Gq-protein and phospholipase Cβ (mediates glycogenolysis in liver) reversal of glucagon-stimulated phosphorylation of enzymes 1. reduciton of cAMP levels 2. stimulation of phosphodiesterase 3. production of specific protein (insulin factor) 4. release of second messanger from bound glycosylated phosphitidylinositol 5. phosphorylation of enzymes at a site that antagonizes PKA phosphorylation repression Phosphoenolpyruvate Carboxykinase Glucagon Insulin an insulin sensitive hormore response element (IRE) in the promotoer region of genes

Biochemistry - Chapter 43 Somatostatin inhibits the release of what two hormones?

Somatostatin is secreted from what cells of the pancreas? Prosomatostatin has how many amino acids in the chain? In the gut, prosomatostain is predominant - what percentage of immunoreactivity does it make up? Prosomatostatin is how many times more potent than somatostatin at inhibiting GH and Insulin? Does insulin directly influence somatostatin secretion? What substance do increase somatostatin secretion? Somatostain receptors are part of what family? How many somatostatin receptors have been identified? How many do not distinguish between SS14 and SS28? When somatostatin binds what is inhibited? No cAMP or PKA results in what, with regards to TSH and GH Somatostatin inhibits what in the GI tract? Basically, somatostatin exerts a broad, albeit indirect, inflence on what? IGFs are also known as what? Somatomedins are produced in response to what? Gene for GH is located on what chromosome? GH is structurally similar to what two hormones? Where are the IGF independent actions of GH exerted primarily? GH adminstration is followed by what? Expression of what gene that is active in polyamine synthesis, is significantly increased by GH? GH has insulin like effects in what type of tissue? GH has growth promoting effects in what type of tissue? GHRH is produced exclusively in cells of the? Full biological activity of GHRH resides where? cAMP and calmodulin both stimulate what? What feeds back negatively on the somatotrophs to limit GH secretion? Rising level of glucose in the blood does what to GH? Hypoglycemia does what to GH? AA concentration rise will do what to GH secretion? FA have a duel effect on GH secretion, describe this. Increases the sensitivity of the adipocyte to lipolytic action of the catecholamines? Decreases the sensitivity to the lipogenic action of insulin? GH leads to the release of what from adiocytes? Where do the FA and glycerols travel for metabolization? The clinical course of acromegaly may be complicated by impaired tolerance to what? When GH causes the release of free FA for fuel, these FA bathe what? The muscle then uses these as fuel, and spares what other fuel source? What effect does GH have on AA and muscle tissue? Protein sparing effect of GH-induced lipolysis that makes FA availabe as a fuel source, does what to nitrogen balance? When insulin is low, GH does what to FA oxidation -> acetyl CoA? Increased amount of glycerol reaching the liver, is used as substrate for what process?

GH Insulin Glucagon (indirectly) D-Cells 28 (SS-28) 70-75% 7-10 times No Glucose, Argininine, Leucine, Glucagon, VIP, CCK G coupled proteins 5 4 Production of cAMP and PKA Suppression of secretion of GH and TSH Gastrin Pancreatic enzyme secretion Nutrient Absorption Somatomedins GH binding to plasma membrane receptors 17 Human Prolactin and Human Chorionic Somatomammotropin (hCS) Hepatocytes An early increase in 8-10 proteins, among which are IFG-I, α2-macroglobulin, and serine protease inhibitors Ornithine Decarboxylase Adipose Muscle Arcuate Nucleus in the first 29 AA of the N-terminal portion GH release IGF-1 (produced in the liver, in response to GH secretion) Decreases GH secretion Increases GH secretion Increases GH secretion FA release can decrease GH secretion due to increased AA or hypoglycemia. However, Prolonged fasting utilizes FA increases GH. GH GH Free FA and Glycerol Liver Insulin The muscle Glucose (and glucose uptake) Increases the rate of AA uptake by muscle -> substrate for protein synthesis Has a positive effect on nitrogen balance Enhances it, thus enhancing ketogenesis Gluconeogenesis

GH has what effect on glucose metabolism? Major effect of GH on the liver? Two somatomedins that share homology with proinsulin? In normal cells, high doses of insulin can cause inceased ________ uptake and initiate cell propogation? Causes the same response as insulin in these cells, but at significally smaller physiologic concentrations? IGFs are more/less potent than insulin in the their growth promoting actions? Which IGF has intrinsic tyrosine kinase ability? What initiates the process of cellular replication and growth? Most cells have mRNA for IGF but what organ has the most? Sythesis of IGF-I is regulated by GH, is hepatic production of IGF-II related to GH? What catecholamine is primariliy synthesized in the adrenal medulla? What catecholamine is sythesized in the adrenal medulla and various areas of the CNS? What catecholamine acts primarily as a NT and has little effect on feul metabolism? Sutherland was the first to show that epinephrine does what? Precursor to catecholamines? High levels of circulating what have been linked to the development of breats, colon, and lung cancer? Mediated by stress-induced transmission of nerve impulses emanating from adrenergic nuclei in the hypothalamus? Which NT is activated by stress that causes the preG neurons that innervate the adrenal medulla to depolarize? Synthesis and release of catecholamines come from where? Counter-regulatory hormones have metabolic effects directed toward the? What else do these counter regualtory hormones do, at the same time as mobilize fuels? What are the noted metabolites of catecholamines that can be measured in a urine sample? Symptoms of excessive sweating, palpitations, tremulousness, and hypertension? Glucocorticoids were named for the their ability to do what? Nonspecific stresses elicit the production of what from the cell bodies of the neurons of the midbrain? Those monoamines stimulate the release of what? The major trophic influence of ACTH on corticol synthesis is at the level of the conversion of what to what? Free and unbound ACTH bathing the cells of the hypothalamus acts as a what? In times of severe stress, the negative feedback mechanism for coritsol can be what? Why do patients with a pheochromocytoma develop hyper-glycemia? Glucocortoids (GCs) do what in different tissues?

When GCs are elevated, what happens to glucose uptake by the cells of many tissues? Why does this occur? If the levels of PEPCK is increased, what does that signal the liver to do? Effect of GCs on muscles? Primary neoplasm of the adrenal cortex will cause what to happen the levels of ACTH and cortisol, respectively? Where is the protein thyroglobulin synthesized? Where is the protein thyroglobulin secreted into? Iodine trapping mechanism is poorly defined but may involve an?

It surpresses it at numerous steps in the glycolytic pathway Stimulate sythesis and release of IGF (somatomedins) IGF-I (somatomedin C) IGF-II (somatomedin A) Thymidine IGF-I (somatomedin C) More IGF-I (somatomedin C) Tyrosine phosphorylation Liver No, it is independent of GH NE E Dopamine Induces glycogenolysis Tyrosine IGF-1 Release of catecholamines ACH Chromaffin granules Mobilization of feuls Suppress insulin secretion Metanephines and vanillylmandeilic acid Catecholamine excess (pheochromocytoma) Raise blood glucose levels Monoamines CRH, serotonin and ACH Cholesterol to pregnanolone Negative feedback Overidden by the sress induced activity of the higher portions of the axis NE and E provide substrate for gluconeogenesis - they also surpress insulin secretion Liver: promote gluconeogenesis(increase precursors and PEPCK) and glycogen storage Muscle: promote protein degradation and inhibit: protein synthesis and glucose utilization by muscke Adiose: increase lipolysis and decrease glucose utilization Glucose uptake is inhibited It occurs so that glycogen storage is increased, so when the alarm sounds - the body can utilize fuel quickly for fight or flight Increase Gluconeogenesis Protein catabolism will increase, will see some muscle wasteing ACTH will be depressed (negative feedback) and cortisol will be elevated (primary overproduction) Thyroid follicular cells Colloid NA+K+ ATPase couple cotransporter for Na+ and iodine in the plasma membrane of the acinar cell

Oxidation of intracellular iodide is catalyzed by what? Believed to be the predominant biologically active form of thyroid hormone in the body? Which has a longer plasma half-life, t3 or t4? Why is T3 the biologically active form? How/where are thyroid hormones degraded? What hydroloyzes thyroglobulin to release free T3 and T4 into the blood in a 10:1 ration? Binding of TSH to the specific receptor on the thyroid acinar cells leads to an increase in what? Deficiency of iodine will usually lead to what? Normal metabolic effects of thyroid hormone on different tissues:

What is the "incretin" effect? Enhance the synthesis and release of insulin while promoting the survival of islet cells? Contributes to the regulation of glucose by inhibiting the secretion of glucagon/slows rate of gastric empty? Interacts with GIP receptors on adipocytes (interaction coupled with energy storage)? Orally administered inhibitor of DPP4, that slows the rate catalytic cleavage of GIP and GLP-1 by DPP4. Prolongs GLP1 and GIP in blood, therefore this medication can be administered how many times/day? Insulin secretion is increased by stimulation of what nerve and decreased by stimulation of what nerve, respectively? Stimulation of what systems of nerves will increase glucagon secretion? Of the two basic receptors (CB1 and CB2), which one is involved with energy homeostasis? CB1 receptor blockade has been shown to decrease what? The most significant reward pathway appears to be part of the? Blockade of the hepatic ECS protects the liver from the damaging effects of what? CB1 receptor blockade may stimulate thermogenesis and increased oxygen consumption in? For GH, secretory stimulants include:

To test for acromegaly using a suppression test, criteria must be met?

With RIA, the higher the amount of unlabeled hormone in the sample, the less… what?

Thyiod peroxidase T3 t4 (7 days) It is free and unbound, therefore it can diffuse across target cell membranes to interact with intracellular receptors Liver, kidney, muscle and other tissues via deiodination -> produces compounds with no bio activity lysosomal proteases cAMP, it also increases the level of inositol trisphosphate and diacylglycerol -> cytosolic Ca2+ w/in the thyroid cell Goiter, in an attempt to produce more thyroid hormone. Liver: increase glycolysis, cholesterol synthesis, and conversion of cholesterol into bile salts Adipose: amplifies the effect of E on fat cells but also increases the availability of glucose to fat cells Muscle: increases glucose uptake by muscle cells and stimulates protein synthesis - growth of muscle Pancreas: increases sensitivity of β-cells to stimuli that normally promote insulin secretion greater β-cell response seen after an oral glucose load, as opposed to one that is adminstered IV GLP-1 and GIP GLP-1 GIP Sitagliptin Twice Vagus (increased) and sympathetic fibers (decreased) Both adrenergic and cholinergic limbs of the ANS CB1 The "reward" potential of addictive drugs Mesolimbic-dopaminergic system A high fat diet Adipocytes 1. Nutritional Factors 2. Level of activity 3. Consciousness 4. Stress 5. High protein meal 6. Low level of FA or glucose in the blood 7. Vigorous exercise 8. Sleep 9. Stress 10. Levadopa 11. Clonidine 12. Estrogens 1. Patient must not have eaten for 6-8 hours 2. Patient must not have done any vigorous exercise for at least 4 hours 3. Patient must remain fully awake for the duration of the test 4. Patient must not have taken any drugs that increase GH for at least 1 week The less radiolabeled hormone is bound

In IRMAs, the same process is used but what is radiolabled? RIAs can be enhanced using the sandwich technique, explain?

The antibody, rather than the antigen is radiolabeled two different monoclonal antibodies, each recognizes a different portion of the hormone structure

Biochemistry - Chapter 48 Most abundant type of cell in the nervous system? Glial consists of? Astrocytes and Oligodendrocytes are found in the Shwann Cells are found in the? These cells provide support and synthesize what? The myelin sheath surrounds the ? Act as immune cells in the NS, destroying and ingesting foreign organisms? Interface between brain parenchyma and CSF are the? Where are they found? These cells use their ______ to move the CSF, which bathes the cells of the CNS Neurons are terminallly ______ and have very little capability for division Astrocytes are found in the CNS and are ____ shaped? Regulate the EC environment: taking up, processing, and metabolizing nutrients and waste products? Provide the myelin sheath that surrounds the axon? Oligodendrocytes can form myelin sheaths around multiple neurons by sending out what? If oligodendrocyte is damaged it will not _______ Supporting cells of PNS that can myelinate only one axon? Damaged PNS axons can do what with their appropriate targets post-damage? Blood Brain Barrier:

Endothelial cells protect the brain in two important ways:

Glucose is transported across the BBB via? Glucose is transported into the neuron via? Glial cells express which GLUT? As the glucose level is reduced to or past the Km for the GLUT1 transporter, patient will Are important sources of fuel for the brain of both adults and neonates in starvatoin? During starvation the transporter for ketone bodies will be? Disorder where transporters are impaired, results in low glucose concentration in the CSF? Low glucose concentration in the CSF is called? Diagnostic information for GLUT1 Deficiency? Treatment for GLUT1? Symptoms of GLUT1 Deficiency? LNAAs share what that can lead to competitive antagonism for entry between Aas? Small AA are restricted entry due to the fact that they could change content of NTs, how do they get in the brain? Treatment of patients with PKU with high levels of LNAA that lacks Phenylalanine proved that? Two categories of NTs? Neuronal tracts are usually identified by what? Usually small peptides that are synthesized and processed in the CNS? Some have targets within the CNS, like this one? Others are released into circulation, like these?

Glial Astrocytes and Oligodendrocytes CNS PNS Myelin Axon Microglial cells Ependymal cells Lining the cavities of the brain and spinal cord Cilia Differentiated Star Astrocytes Oligodendrocytes Processes that bind to axons on target neurons replicate Schwann Cells Reconnect 1. Tight Junctions at endothelial cells - no polar molecules 2. Narrow intercellular spaces 3. Lack of pinocytosis 4. Continuous Basement Membrane 5. Astrocyte Extension 1. Enzymatically 2. P-glycoproteins = actively pump hydrophobic molecules back into the blood from the endo cell GLUT-1 GLUT-3 GLUT-1 Experience hypo-glycemic symptoms Ketone Bodies Up-regulated GLUT1 deficiency hypoglycorrhachia CSF Glucose to Blood Glucose Ratio of less than .4 High Fat, Low Carb diet -> force the body to use Ketone Bodies as fuel Seizures, developmental delay, and complex motor disorder BBB transporter They are synthesized there Proved that competitive antagonism via other AA can lower levels of phenylalanine in the brain, and improve symptoms 1. Small Nitrogen-containing NTs 2. Neuropeptides The specific neurotransmitter that they use Neuropeptides Endorphins -> bind to opioid receptors and block pain signals TSH and GH

Most are synthesized as what? Differential release of various NTs from one neuron is a result of? Synthesized from AA, intermediates of glycolysis and TCA and O2 in the cytoplasm of the preS membrane? Rate of synthesis corresponds to rate of? Once synthesized, NTs are stored in vesicles by what? Release of the storage vesicle is triggered by the nerve impulses that? What does Ca2+ promote? Four ways to terminate action of the NT?

Does NO exhibit these characteristics? Antihypertensive/Antiepileptic that blocks (catecholamine) NT uptake into storage vesicles? The side effect of depression noted with reserpine forged a connection between what and depression? Dopamine, E, and NE are all synthesized from what AA? Where do we get tyrosine? Phenylalanine -> Tyrosine? L-Tyrosine -> LDOPA? LDOPA -> Dopamine? Dopamine -> NE? NE -> E? Defective Tyrosine Hydroxylase will lead to what disease condition? Conversion of Tyrosine to LDOPA and LDOPA to dopamine occurs where? β-Hydroxylation occurs where? Transports catecholamines into storage vesicles? Concentration of catecholamines in the vesicles occurs via? Protons are pumped into the vesicle, then exchanged for postitively-charged catecholamines via? Within the vesicles NT are complexed with what? Catecholamines are available for immediate release upon influx of what ion? Do catecholamines always act on nearby neurons? Required for the biogenesis of the storage vesicles? What is proteolytically clipped to form bioactive peptides? Patients with neuroendocrine tumors such as a ____________ would have high circulating levels of chromogranins. Present on outer mitochondrial membrane and oxidizes the amino group to an aldehyde -> rel. ammonium ion? MAO inactivates catecholamines that are not protected by what? Drugs that deplete storage vesicles do what? Preferentially deaminates NE and serotonin? Acts on a wide spectrum of phenylethylamines? MAO in the liver protects against ingestion of what? Tranfers methyl from SAM to catecholamine and is works on a broad spectrum of catechols that diffused away? COMT is dependent on? Cerebrospinal HVA is an indicator of ________ degradation? Cerebrospinal HVA would be increased/decreased in a patient with Parkinson's? Tyrosine Hydroxylase is inhibited by what?

Larger precursor -> then proteolytically cleaved the neuron altering its frequency and pattern of firing NTs Neuronal Firing An ATP dependent pump linked with the proton gradient Depolarize the PostS membrane and cause Ca2+ influx Fusion of the vesicles with the PreS membrane and RELEASE of the NT 1. Uptake into the PreS terminal 2. Uptake into the Glial cells 3. Diffusion away from the synapse 4. Enzymatic Inactivation *may occur in PreS terminal or adjacent astrocyte microglia or in endothelial cells in the brain caps. No, it is a gas, so it is an exception to these rules. Reserpine Monoamine release L-tyrosine Supplied in the diet or synthesized by the liver (from the essential AA phenylalanine) Phe Hydroxylase Tyrosine Hydroxylase Dopa Decarboxylase (requires PLP) Dopamine β-hydroxylase (mixed fx oxidase that needs electron donor, ascorbic acid) Phenylethanol amine N-methyl Transferase (needs SAM, and adequate levels of B12 and folate) Albinism Cytosol Within the vesicles VMAT2 (12 transmembrane domains) ATP-dependent process linked to a proton pump (V-ATPase) VMAT2 ATP and acidic proteins (chromogranins) Ca2+ No, initiate responses in peripheral tissues via travel through the blood Chromogranins Chromogranins Pheochromocytoma MAO Storage Vesicles Indirectly deplete catecholamines via MAO degradation MAO-A MAO-B Dietary Biogenic Amines (tyramine found in cheese) COMT B12 and folate Dopamine Decreased Free cytosolic catecholamines that compete for binding sites on the enzyme for pterin cofactor (BH4)

Depolarization of the nerve terminal activates what enzyme? The kinases that are also activated make the enzyme more sensitive to BH4, and what? Long-term regulatory process involves increased gene transcription via phosphylation of what? Which enzyme is unaffected by the increased gene transcription of enzymes for NE/E synthesis? Degradation product of Tyrosine that can lead to palpitations, nausea, vomitting, and elevated BP? Where does tyramine bind? What is tyramine inactivated by? Patients taking what medication should avoid any foods containing tyramine? Pheochromocytoma will cause elevated levels of catecholamines in blood and? α1 and α2adrenergic receptor antagonist that blocks pharmacologic effect of the elevated catecholamines? Tryptophan -> 5-hydroxytryptophan? 5-hydroxytryptophan -> Serotonin? Inactivates Serotonin? Melatonin is produced from? Melatonin is made in what gland? What is melatonin synthesis linked to? MAO-A selective irreversible inhibitor? MAO-B selective irreversible inhibitor? Parkinson's is caused by a lack of what? What can also be used to treat Parkinson's? Third Generation MAOI? Because it's reversible, Moclobemide allows tyramine to be able to displace the drug from MAO… leads to? Family of bone marrow-derived secretory cells that store and release high concentrations of histamine? They are prevelant where? Histadine -> Histamine? Histamine can activate both? Histamine does not appear to be ________ in the preS terminal to any great extent? What cells have a high affinity uptake system for histamine - may be the major site of degredation? First step in Histamine inactivation? Second step in histamine inactivation? Low serotonin levels cause what? Acted as an SSRI but also increased the secretion of serotonin -> elevated levels of this compound in the synapse? 1st, 2nd, and 3rd Generation Antidepressants were called? Histamine released from mast cells causes? Histamine released in the lungs causes? Histamine is an __________ NT? Acetyl CoA + Choline -> ACH? Choline is taken up from blood and cleft with what affinity, respectively? Choline is derived from hydrolysis of? Route for choline synthesis? Conversion of the following pathway is dependent upon? Acetyl group comes from? Where is pyruvate dehydrogenase found? Serine esterase that forms a covalent bond with acetyl groups, inactivating ACH?

Tyrosine Hydroxylase End product inhibition CREB Dopamine Decarboxylase Tyramine NE receptors MAO-A MAOIs Urine Phenoxybenzamine Tryptophan Hydroxylase PLP + Dopa Decarboxylase MAO Tryptophan Pineal Gland Light/Dark Cycle (increases in the dark) Clorgyline Deprenyl Dopamine Deprenyl Reversible, Moclobemide No Cheese Effect Mast Cells In the thalamus, hypothalamus, dura mater, leptomeninges and choroid process Histidine Decarboxylase + PLP PreS and PostS receptors Recycled Astrocytes Methylation via histamine methyltransferase Oxidation via MAO-B Increased Appetite and Decreased Mood (Depression) Redux MAOIs, Tricyclics, and SSRIs Vasodilation and Increased Permeability of Blood Vessels Airways to constrict in an attempt to reduce the intake of allergic material Excitatory ChAT (in the preS terminal) Low and High Phosphatidylcholine and Sphingomyelin Add 3 methyl from SAM to ethanolamine end of phosphatidyethanolamine -> phosphatidylcholine -> hydrolyzed to choline B12 and folate Glucose -> Pyruvate and decarboxylation of Pyruvate -> Acetyl CoA ONLY in Mitochondria AChE

Sarin Gas is a neurotoxin that uses Excitatory NT, made de novo from glucose, does not cross the BBB, and synthesized from α-keto-glutarate? Two routes to make Glutamate? Glutamine is synthesized from glutamine using? Glutamine derived from? Major inhibitory NT in CNS? GABA is synthesized by the? Glutamate -> GABA? GABA is recycled in the CNS via a series of reactions called? Uptake of GABA occurs in what cells? Process for GABA Shunt? Serves as a transporter of glutamate b/n cells in the CNS? Glial cells lack what, and therefore can not make GABA? Used to increase brain ACH in patients suffering from Tardive Dyskinesia (invol. Movement face and tongue) Neonates have a very high demand for what? Maternal milk has high levels of what? Choline synthesis requires B12 and folate, so maternal requirement will be increased/decreased? Inherited pyruvate dehydrogenase deficiency, thiamine deficiency, or hypoxia leads to what? Inhibits reuptake of GABA from the synapse, used to treat epilepsy (prolonged presense -> stops convulsions)? Excitatory NT, synthesized from TCA intermediate Oxceloacetate? Major inhibitory NT in the SC? Synthesized de novo from Serine -> Glycine via? Where does serine come from? How does glycine get terminated? What is required for choline synthesis, and a lack of this may contribute to neurologic deficits? Biological messanger in a variety of physiologic respones (vasodilation, NT, ability of immune system) NO is synthesized from what? What catalyzes Arginine -> NO? NO synthase is tissue specific, what two forms/actions does it have? NO can activate what on target cells? NO can activate what on smooth muscle cells? Stimulates penile erection by acting as a NT -> stimulate smooth muscle relax -> corpus cavernosum to fill with blood? There is evidence that NO may act as a _______ _______, stimulating NT release from the PreS. Brain uses approximately __% of oxygen supply of the body? Anaerobic Glycolysis yeilds how many ATP? Complete oxidation of Glucose -> CO2 can yeild approximately how many ATP? Encountered in medical conditions such as insulinomas, insulin like growth factors, or chronic alcoholism? What does the brain begin to use as glucose levels fall below 2.5 mM? When do ATP stores become completely depleted? What happens to the EEG as the glucose levels fall below 1 mM?

AChE Glutamate 1. Glutamate Dehydrogenase (reduces α-ketoglutarate -> glutamate) - incorporates free ammonia into backbone 2. Transamination reactions (AA -> α-keto -> glutamate) Glutaminase Glial Cells GABA Decarboxylation of glutamate Glutamic Acid Decarboxylase GABA Shunt (converse GABA and Glutamate) Glial GABA shunt in glial -> glutamate -> glutamine -> transported out of glial -> neurons -> converted back to glutamate Glutamine GAD Lecithin supplementation ACH Phosphatidycholine Increased Deprives the brain of a source of acetyl CoA Tiagabine Aspartate Glycine Serine Hydroxymethyltransferase (requires Folic Acid) The intermediate 3-phosphglycerate in the glycolytic cycle High affinity uptake transporter Vitamin B12 NO Arginine NO synthase 1. Macrophage Form - overproduction of NO -> cytotoxic actions on paracites/tumor cells 2. Nervous Tissue Form - Physiologic action of NO -> vasodilation and neural transmission guanylate cyclase -> cGMP cAMP -> kinases -> relaxation of smooth muscle and dilation of vessels NO Retrograde messenger 20% 2 molecules 32 molecules Hypoglycemia TCA intermediates and glutamate - these are quickly depleted Glucose level below 1 mM EEG become isoelectric -> neuronal cell death ensues

What brain areas are notably vulnerable to hypoglycemic insult? Pathophysiologic mechanism for neuronal cell death in hypoglycemia? Failure of what results in the build up of glutamate in the cleft and overstimulation of the PostS receptors? Prolonged Glutamate receptor stimulation yeilds what? Mild hypoxia results in severe congnitive dysfunction, due to what? In mild hypoxia, what happens to cerebral blood flow? In mild hypoxia, what happens to anaerobic glycolysis? Inhibition of what (highly sensative to hypoxia) results in diminshed acetylcholine synthesis? In hypoxia, why are glutamate and GABA levels decreased? Degradative pathway of the branched AA -> succinyl CoA to the TCA uses what? BBB restricts entry of what type of lipids? Which lipids are the exception due their essential nature? Is important in the brain because the brain contains very-long chain FA and phytanic acid? Disorder that effects peroxisome biogenesis (unable to metabolize branched chain and VL chain FA)? PNS cells that make the myelin sheath? Schwann cell wraps itself around the axon multiple times to create what? CNS cells that myelinate multiple axons? Extends this process that wraps around the axons of many neurons? Axons in the PNS are surround by what? Constitute approximately 16% of total myelin lipid and are completely absent from other cell type memb. Lipids? Predominant cerebroside? In the CNS, which two proteins constitute 60-80% of the total proteins? In the PNS, the major myelin protein is what? Where is the incidence of MS completely nil? Primary injury to the CNS in MS is loss of what in the white matter? What does the disease stimulate to go into remission? Inherited mutations in Po (PNS) leads to a version of what disease? Mutations in PLP lead to what disease process? Altered function of Po or PLP leads to what?

Hippocampus and Cortical Structures Glutamate Excitotoxicity Energy dependent reuptake pumps Open receptor ion channel -> influx of lethal levels of Ca2+ -> cytotoxic intracellular pathways in the postS neuron Impaired NT synthesis Increases to deliver more 02 Increases -> more ATP -> also increased lactate production and fall in pH Pyruvate dehydrogenase elevated NADH levels -> inhibit TCA (O2 unavailable to accept electrons from e transport chain) B12 (not folate) and is catalyzed by methylmalonyl CoA mutase Non-essential FA Linoleic and Linolenic Acid Peroxisomal FA oxidation Refsum Disease Shwann Cells Multilayered sheath of membrane Oligodendrocytes Oligodendrocytes The entire schwann cell Cerebrosides Galactosylcerebroside PLP and MBPs - both soluble in water and attracted to the membrane Po, plays similar role in maintaining myelin structure as PLP does in the CNS At the equator Myelin Oligodendrocytes Charcot-Marie-Tooth polyneuropathy syndrome - Autosomal Dominant Pelizaeus-Merbacher Disease and X-Linked spastic paraplegia type 2 disease Demyelination and its subsequent manifestations