Biochemistry - Chapter 26

Control of balance between substrate need and substrate availability is known as?Metabolic Homeostasis

Three ways that intertissue integration for metabolic homeostasis is achieved?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

Determines whether skeletal muscle will use fatty acids or glucose as fuelConcentration of FA

Two major hormones that regulate fuel storage and mobilization?Insulin and Glucagon

Major anabolic hormone of the body?Insulin

Promotes storage of fuels and utilization of fuels for growth?Insulin

Major hormone of fuel mobilization?Glucagon

Minimum amount of glucose required a day for an adult?190 g (150 for brain, 40 for other tissues)

Cutoff for absolute minimum amount of blood glucose before hypoglycemic episodes?60 mg/dL

Overall process of glucose flux through the BBB -> into interstital -> neuronal cells is ____ at low blood glucose levels?Slow

Effects that would occur if even a day's worth of glucose, AA, and FA's could not enter cells normally?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

Hormone that acts to inhibit fuel mobilization?Insulin

Nonenzymatic glycosylation slows protein __________?Degradation

Action of Insulin in Adipose Tissue?Promotes Glucose -> FA and FA -> TAGs (inhibits TAGs -> FA)

Action of Insulin Skeletal Muscle?Promotes AA -> Proteins and Glucose -> Glycogen and CO2

Action of Insulin in the Liver?Promotes Glucose converstion to Glycogen and FA; also promotes AA -> Proteins (inhibits catabolism and gluconeogenesis)

Action of Glucagon in Adipose Tissue?Promotes TAGs -> FA (for fuel) and subsequent FA release from Tissues

Action of Glucagon in Skeletal Muscle?No Effect

Action of Glucagon in the Liver?Promotes Glycogen -> Glucose, AA -> Glucose (Gluconeogenesis), and Glucose release from Liver (inhibits storage of glucose)

After high glucose meal, a graph of insulin release will show what?Insulin Spike and Glucagon Fall

What tissue lacks glucagon receptors?Skeletal muscle

When do the highest levels of insulin occur?Approx. 30-45 minutes after a meal

Action of E, NE, and cortisol on metabolic homeostasis?oppose the actions of insulin by mobilizing fats

Release of cortisol, E, and NE are controlled by what?Neuronal signals

Release of Insulin and Glucagon controlled by what?direct response to changing levels of fuels in the blood

Action of E on Muscle and Liver?Stimulates glucose production from glycogen

Action of E on Adipose Tissue?Stimulates FA release from Adipose Tissue

Action of Cortisol on Muscle?Catabolism of Muscle protein for AA release

Action of Coritsol on Adipose?Stimulates FA release from Adipose Tissue

Action of Cortisol on Liver?Stimulates usage of AA for gluconeogenesis

Which counter regulatory hormone is released for fuel mobilization during periods of ACUTE stress?Epinephrine

Which counter regulatory hormone is released for fuel mobilization during LASTING periods of stress?Cortisol

What stimulates the adrenal medulla to release Cortisol and E?ACTH (from Anterior Pituitary)

What stimulates the release of NE?ANS

What stimulates the release of Glucagon from the -cells of the pancrease?Low Blood Glucose and ANS (minor role in the release of glucagon)

Message conveyed by the release of insulin to the body?Glucose is plentiful and available for use as fuel or storage

An Insulinoma is what?A tumor that produces excessive insulin

Production of excessive insulin would result in?Reduced blood glucose levels due to uptake into tissues

Glucagon and Insulin are secreted by the endocrine pancreas directly into what vessel?Hepatic Portal Vein (via the pancreatic veins)

Insulin is a polypeptide hormone composed of how many chains?Two

How many disulfide bonds are in the active form of insulin?3, two interchain and 1 intrachain (A-chain)

Insulin is synthesized as a prehormone that is converted to proinsulin in what organelle?rER

Disulfide bonds are formed between what two AA?Cysteine residues

Where does a protease cleave the C-Peptide from proinsulin -> active insulin?In the storage vesicles secreted by the Golgi

What else is transported in these vesicles?Zinc

Glucose enters the -cell through what glucose transporter?GLUT2

Glucose is phosphorylated to form what?G6P

G6P is then ________ through glycolysis -> TCA -> oxidative phosphorylationmetabolized

These reactions result in what within the -cell?Increased ATP

As -cell ATP/ADP ratio increases, what happens the K+ channel?It is inhibited

Closing of the channel leads to what?Membrane Depolarization

Depolarization of the membrane activates what?Ca2+ channel

Ca2+ rushes in, and stimulates what?Fusion of the insulin-containing transport vesicles with the PM

As insulin is secreted, what occurs at the same time?Synthesis of new insulin

AA can stimulate insulin secretion, although the amount of insulin released during high protien meal is what?Less than the amount released during a high carb meal

Examples of Gut hormones that can also trigger insulin release?GLP-1 and GIP (released after ingestion of food)

Preproglucagon is produced where?In the rER

Where it preproglucagon converted to proglucagon?Lumen of the ER

Glucagon is rapidly metabolized, where?Liver and Kidneys

Plasma half-life of glucagon?3-5 minutes

Increasing levels of insulin and glucose, will inhibit what?Release of glucagon

Direction of blood flow in the pancreas carries insulin to where?-cells (they are downstream from the -cells)

What is a major positive regulator of glucagon release?Amino Acids

Other minor positive regulators of glucagon release include?Catecholamines

In a normal individual, as blood glucose levels drop, what else happens?insulin levels drop

High protein meal would cause what to happen to insulin and glucagon release?Insulin would rise (not as much as after carbo meal) and glucagon would show great increase (well above fasting)

Type 1 diabetes is caused by what?Antibody mediated destruction of -cells

Susceptability for Type 1 diabetes, conferred how?genetic defect in the gene that codes for MHC II (self recognition)

MODY type 2 is due to what type of mutation?glucokinase mutation that results in an ezyme with a elevated Km (lower affinity for glucose - less efficient)

MODY patients can release insulin only at what glucose levels?higher than normal

Therefore, MODY patients are usually always in what state?Hyperglycemic State

Neonatal diabetes is an inherited disorder in which newborns develop diabetes, when?Within the first 3 months of life

What mutation results in neonatal diabetes?KCNJ11 gene mutation

What kind of mutation is KCNJ11?Activating mutation for the K+ channel

This mutation does what to the K+ channel?keeps it open, and less susceptable to the ATP inhibition -> no Ca2+ channel activation -> no insulin secretion

Mutation of the SUR1 gene would make what difficult?Make it difficult to close the K+ channel -> display neonatal diabetes

What can one use to determine the rate of insulin secretion in a patient with a insulinoma?C-peptide, it is not cleared from the blood as rapidly as insulin

Can you use this measurement for diabetes mellitus patients as well?Yes, because exogenous insulin does not contain C-peptide

Patients with Type 1 diabetes have increased/decreased levels of insulin in their blood?Decreased, or barely existant

Patients with Type 2 diabetes have what level of insulin in their blood?Normal or elevated, but it is not enough to combat the hyperglycemia

Insulin Mechanism for Receptor Binding?Insulin binds to subunit -> spans the membrane -> TK phophorylates tyrosine residues on (autoP) -> IRS1 phosphorylated ->

IRS-1 binds to SH2 domains

Five basic tissue-specific reponses to insulin: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

5. insulin stimulates glucose and AA transport into cells

Mechanism for Glucagon reaction when bound to receptor?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

In the absense of glucagon bound to the receptor, what happens?Gs-protein complex binds GDP but can't bind unoccupied receptor or Adenylate cyclase

Only what can keep the adenylate cyclase active?continued occupancy of glucagon receptor

What tissue has NO glucagon receptors?Skeletal muscle

What degrades cAMP?Membrane-bound phosphodiesterase

What inhibits phosphodiesterase?Methylxanthines, class of compounds that includes caffeine

Any steroid hormones (cortisol) involve direct binding of the hormone where?in the nucleus, where it interacts with chromatin

Chronic stress of sepsis results in what?varying degrees of glucose intolerance, if high levels of E and cortisol are present

Cortisol and Glucagon all increase the rate of gene transcriptio for enzymes in what pathway?Glucose synthesis from AA (gluconeogenesis)

With regards to NE and E, which receptors work through the adenylate cyclase-cAMP system?1, 2, 3

What do they activate?Gs Protein -> adenylate cyclase -> cAMP -> PKA

1 acts where?Human Heart

1 majorly stimulated by?NE

Activation of 1 receptor does what?Increases rate of muscle contraction due to PKA-mediated phosphorylation of phospholamban

2 acts where?Liver, Sk. M and other tissues involved in fuel mobilization

2 also mediates what?vascular, bronchial, and uterine smooth muscle contraction

Which is more potent agonist for the 2 receptor, NE or E?Epinephrine

3 is found primarily where?Adipose tissue

Activation of the 3 stimulates what?FA oxidation and thermogenesis

Agonists for this receptor may prove to be beneficial for what?weight-loss

1 are postsynaptic receptors, mediate vascular and smooth muscle contraction, and work through what system?Phosphatidylinositol bisphosphate system via activation of Gq-protein and phospholipase C- (mediates glycogenolysis in liver)

One of the important cellular responses to insulin is what?reversal of glucagon-stimulated phosphorylation of enzymes

Mechanisms for this include: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

Insulin causes __________ of of the synthesis of enzymes that are induced by glucagonrepression

Key enzyme in the gluconeogenic pathway?Phosphoenolpyruvate Carboxykinase

Phosphoenolpyruvate Carboxykinase is increased by what?Glucagon

Phosphoenolpyruvate Carboxykinase is decreased by what?Insulin

Antagonism is exerted throughan insulin sensitive hormore response element (IRE) in the promotoer region of genes

Biochemistry - Chapter 43

Somatostatin inhibits the release of what two hormones?GH

Insulin

Glucagon (indirectly)

Somatostatin is secreted from what cells of the pancreas?D-Cells

Prosomatostatin has how many amino acids in the chain?28 (SS-28)

In the gut, prosomatostain is predominant - what percentage of immunoreactivity does it make up?70-75%

Prosomatostatin is how many times more potent than somatostatin at inhibiting GH and Insulin?7-10 times

Does insulin directly influence somatostatin secretion?No

What substance do increase somatostatin secretion?Glucose, Argininine, Leucine, Glucagon, VIP, CCK

Somatostain receptors are part of what family?G coupled proteins

How many somatostatin receptors have been identified?5

How many do not distinguish between SS14 and SS28?4

When somatostatin binds what is inhibited?Production of cAMP and PKA

No cAMP or PKA results in what, with regards to TSH and GHSuppression of secretion of GH and TSH

Somatostatin inhibits what in the GI tract?Gastrin

Pancreatic enzyme secretion

Basically, somatostatin exerts a broad, albeit indirect, inflence on what?Nutrient Absorption

IGFs are also known as what?Somatomedins

Somatomedins are produced in response to what?GH binding to plasma membrane receptors

Gene for GH is located on what chromosome?17

GH is structurally similar to what two hormones?Human Prolactin and Human Chorionic Somatomammotropin (hCS)

Where are the IGF independent actions of GH exerted primarily?Hepatocytes

GH adminstration is followed by what?An early increase in 8-10 proteins, among which are IFG-I, 2-macroglobulin, and serine protease inhibitors

Expression of what gene that is active in polyamine synthesis, is significantly increased by GH?Ornithine Decarboxylase

GH has insulin like effects in what type of tissue?Adipose

GH has growth promoting effects in what type of tissue?Muscle

GHRH is produced exclusively in cells of the?Arcuate Nucleus

Full biological activity of GHRH resides where?in the first 29 AA of the N-terminal portion

cAMP and calmodulin both stimulate what?GH release

What feeds back negatively on the somatotrophs to limit GH secretion?IGF-1 (produced in the liver, in response to GH secretion)

Rising level of glucose in the blood does what to GH?Decreases GH secretion

Hypoglycemia does what to GH?Increases GH secretion

AA concentration rise will do what to GH secretion?Increases GH secretion

FA have a duel effect on GH secretion, describe this.FA release can decrease GH secretion due to increased AA or hypoglycemia. However, Prolonged fasting utilizes FA increases GH.

Increases the sensitivity of the adipocyte to lipolytic action of the catecholamines?GH

Decreases the sensitivity to the lipogenic action of insulin?GH

GH leads to the release of what from adiocytes?Free FA and Glycerol

Where do the FA and glycerols travel for metabolization?Liver

The clinical course of acromegaly may be complicated by impaired tolerance to what?Insulin

When GH causes the release of free FA for fuel, these FA bathe what?The muscle

The muscle then uses these as fuel, and spares what other fuel source?Glucose (and glucose uptake)

What effect does GH have on AA and muscle tissue?Increases the rate of AA uptake by muscle -> substrate for protein synthesis

Protein sparing effect of GH-induced lipolysis that makes FA availabe as a fuel source, does what to nitrogen balance?Has a positive effect on nitrogen balance

When insulin is low, GH does what to FA oxidation -> acetyl CoA?Enhances it, thus enhancing ketogenesis

Increased amount of glycerol reaching the liver, is used as substrate for what process?Gluconeogenesis

GH has what effect on glucose metabolism?It surpresses it at numerous steps in the glycolytic pathway

Major effect of GH on the liver?Stimulate sythesis and release of IGF (somatomedins)

Two somatomedins that share homology with proinsulin?IGF-I (somatomedin C)

IGF-II (somatomedin A)

In normal cells, high doses of insulin can cause inceased ________ uptake and initiate cell propogation?Thymidine

Causes the same response as insulin in these cells, but at significally smaller - physiologic concentrations?IGF-I (somatomedin C)

IGFs are more/less potent than insulin in the their growth promoting actions?More

Which IGF has intrinsic tyrosine kinase ability?IGF-I (somatomedin C)

What initiates the process of cellular replication and growth?Tyrosine phosphorylation

Most cells have mRNA for IGF but what organ has the most?Liver

Sythesis of IGF-I is regulated by GH, is hepatic production of IGF-II related to GH?No, it is independent of GH

What catecholamine is primariliy synthesized in the adrenal medulla?NE

What catecholamine is sythesized in the adrenal medulla and various areas of the CNS?E

What catecholamine acts primarily as a NT and has little effect on feul metabolism?Dopamine

Sutherland was the first to show that epinephrine does what?Induces glycogenolysis

Precursor to catecholamines?Tyrosine

High levels of circulating what have been linked to the development of breats, colon, and lung cancer?IGF-1

Mediated by stress-induced transmission of nerve impulses emanating from adrenergic nuclei in the hypothalamus?Release of catecholamines

Which NT is activated by stress that causes the preG neurons that innervate the adrenal medulla to depolarize?ACH

Synthesis and release of catecholamines come from where?Chromaffin granules

Counter-regulatory hormones have metabolic effects directed toward the?Mobilization of feuls

What else do these counter regualtory hormones do, at the same time as mobilize fuels?Suppress insulin secretion

What are the noted metabolites of catecholamines that can be measured in a urine sample?Metanephines and vanillylmandeilic acid

Symptoms of excessive sweating, palpitations, tremulousness, and hypertension?Catecholamine excess (pheochromocytoma)

Glucocorticoids were named for the their ability to do what?Raise blood glucose levels

Nonspecific stresses elicit the production of what from the cell bodies of the neurons of the midbrain?Monoamines

Those monoamines stimulate the release of what?CRH, serotonin and ACH

The major trophic influence of ACTH on corticol synthesis is at the level of the conversion of what to what?Cholesterol to pregnanolone

Free and unbound ACTH bathing the cells of the hypothalamus acts as a what?Negative feedback

In times of severe stress, the negative feedback mechanism for coritsol can be what?Overidden by the sress induced activity of the higher portions of the axis

Why do patients with a pheochromocytoma develop hyper-glycemia?NE and E provide substrate for gluconeogenesis - they also surpress insulin secretion

Glucocortoids (GCs) do what in different tissues?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

When GCs are elevated, what happens to glucose uptake by the cells of many tissues?Glucose uptake is inhibited

Why does this occur?It occurs so that glycogen storage is increased, so when the alarm sounds - the body can utilize fuel quickly for fight or flight

If the levels of PEPCK is increased, what does that signal the liver to do?Increase Gluconeogenesis

Effect of GCs on muscles?Protein catabolism will increase, will see some muscle wasteing

Primary neoplasm of the adrenal cortex will cause what to happen the levels of ACTH and cortisol, respectively?ACTH will be depressed (negative feedback) and cortisol will be elevated (primary overproduction)

Where is the protein thyroglobulin synthesized?Thyroid follicular cells

Where is the protein thyroglobulin secreted into?Colloid

Iodine trapping mechanism is poorly defined but may involve an?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?Thyiod peroxidase

Believed to be the predominant biologically active form of thyroid hormone in the body?T3

Which has a longer plasma half-life, t3 or t4?t4 (7 days)

Why is T3 the biologically active form?It is free and unbound, therefore it can diffuse across target cell membranes to interact with intracellular receptors

How/where are thyroid hormones degraded?Liver, kidney, muscle and other tissues via deiodination -> produces compounds with no bio activity

What hydroloyzes thyroglobulin to release free T3 and T4 into the blood in a 10:1 ration?lysosomal proteases

Binding of TSH to the specific receptor on the thyroid acinar cells leads to an increase in what?cAMP, it also increases the level of inositol trisphosphate and diacylglycerol -> cytosolic Ca2+ w/in the thyroid cell

Deficiency of iodine will usually lead to what?Goiter, in an attempt to produce more thyroid hormone.

Normal metabolic effects of thyroid hormone on different tissues: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 -cells to stimuli that normally promote insulin secretion

What is the "incretin" effect?greater -cell response seen after an oral glucose load, as opposed to one that is adminstered IV

Enhance the synthesis and release of insulin while promoting the survival of islet cells?GLP-1 and GIP

Contributes to the regulation of glucose by inhibiting the secretion of glucagon/slows rate of gastric empty?GLP-1

Interacts with GIP receptors on adipocytes (interaction coupled with energy storage)?GIP

Orally administered inhibitor of DPP4, that slows the rate catalytic cleavage of GIP and GLP-1 by DPP4.Sitagliptin

Prolongs GLP1 and GIP in blood, therefore this medication can be administered how many times/day?Twice

Insulin secretion is increased by stimulation of what nerve and decreased by stimulation of what nerve, respectively?Vagus (increased) and sympathetic fibers (decreased)

Stimulation of what systems of nerves will increase glucagon secretion?Both adrenergic and cholinergic limbs of the ANS

Of the two basic receptors (CB1 and CB2), which one is involved with energy homeostasis?CB1

CB1 receptor blockade has been shown to decrease what?The "reward" potential of addictive drugs

The most significant reward pathway appears to be part of the?Mesolimbic-dopaminergic system

Blockade of the hepatic ECS protects the liver from the damaging effects of what?A high fat diet

CB1 receptor blockade may stimulate thermogenesis and increased oxygen consumption in?Adipocytes

For GH, secretory stimulants include: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

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

With RIA, the higher the amount of unlabeled hormone in the sample, the less what?The less radiolabeled hormone is bound

In IRMAs, the same process is used but what is radiolabled?The antibody, rather than the antigen is radiolabeled

RIAs can be enhanced using the sandwich technique, explain?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

Glial consists of?Astrocytes and Oligodendrocytes

Astrocytes and Oligodendrocytes are found in theCNS

Shwann Cells are found in the?PNS

These cells provide support and synthesize what?Myelin

The myelin sheath surrounds the ?Axon

Act as immune cells in the NS, destroying and ingesting foreign organisms?Microglial cells

Interface between brain parenchyma and CSF are the?Ependymal cells

Where are they found?Lining the cavities of the brain and spinal cord

These cells use their ______ to move the CSF, which bathes the cells of the CNSCilia

Neurons are terminallly ______ and have very little capability for divisionDifferentiated

Astrocytes are found in the CNS and are ____ shaped?Star

Regulate the EC environment: taking up, processing, and metabolizing nutrients and waste products?Astrocytes

Provide the myelin sheath that surrounds the axon?Oligodendrocytes

Oligodendrocytes can form myelin sheaths around multiple neurons by sending out what?Processes that bind to axons on target neurons

If oligodendrocyte is damaged it will not _______replicate

Supporting cells of PNS that can myelinate only one axon?Schwann Cells

Damaged PNS axons can do what with their appropriate targets post-damage?Reconnect

Blood Brain Barrier:1. Tight Junctions at endothelial cells - no polar molecules

2. Narrow intercellular spaces

3. Lack of pinocytosis

4. Continuous Basement Membrane

5. Astrocyte Extension

Endothelial cells protect the brain in two important ways:1. Enzymatically

2. P-glycoproteins = actively pump hydrophobic molecules back into the blood from the endo cell

Glucose is transported across the BBB via?GLUT-1

Glucose is transported into the neuron via?GLUT-3

Glial cells express which GLUT?GLUT-1

As the glucose level is reduced to or past the Km for the GLUT1 transporter, patient willExperience hypo-glycemic symptoms

Are important sources of fuel for the brain of both adults and neonates in starvatoin?Ketone Bodies

During starvation the transporter for ketone bodies will be?Up-regulated

Disorder where transporters are impaired, results in low glucose concentration in the CSF?GLUT1 deficiency

Low glucose concentration in the CSF is called?hypoglycorrhachia

Diagnostic information for GLUT1 Deficiency?CSF Glucose to Blood Glucose Ratio of less than .4

Treatment for GLUT1?High Fat, Low Carb diet -> force the body to use Ketone Bodies as fuel

Symptoms of GLUT1 Deficiency?Seizures, developmental delay, and complex motor disorder

LNAAs share what that can lead to competitive antagonism for entry between Aas?BBB transporter

Small AA are restricted entry due to the fact that they could change content of NTs, how do they get in the brain?They are synthesized there

Treatment of patients with PKU with high levels of LNAA that lacks Phenylalanine proved that?Proved that competitive antagonism via other AA can lower levels of phenylalanine in the brain, and improve symptoms

Two categories of NTs?1. Small Nitrogen-containing NTs

2. Neuropeptides

Neuronal tracts are usually identified by what?The specific neurotransmitter that they use

Usually small peptides that are synthesized and processed in the CNS?Neuropeptides

Some have targets within the CNS, like this one?Endorphins -> bind to opioid receptors and block pain signals

Others are released into circulation, like these? TSH and GH

Most are synthesized as what?Larger precursor -> then proteolytically cleaved

Differential release of various NTs from one neuron is a result of?the neuron altering its frequency and pattern of firing

Synthesized from AA, intermediates of glycolysis and TCA and O2 in the cytoplasm of the preS membrane?NTs

Rate of synthesis corresponds to rate of?Neuronal Firing

Once synthesized, NTs are stored in vesicles by what?An ATP dependent pump linked with the proton gradient

Release of the storage vesicle is triggered by the nerve impulses that?Depolarize the PostS membrane and cause Ca2+ influx

What does Ca2+ promote?Fusion of the vesicles with the PreS membrane and RELEASE of the NT

Four ways to terminate action 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.

Does NO exhibit these characteristics? No, it is a gas, so it is an exception to these rules.

Antihypertensive/Antiepileptic that blocks (catecholamine) NT uptake into storage vesicles?Reserpine

The side effect of depression noted with reserpine forged a connection between what and depression?Monoamine release

Dopamine, E, and NE are all synthesized from what AA?L-tyrosine

Where do we get tyrosine?Supplied in the diet or synthesized by the liver (from the essential AA phenylalanine)

Phenylalanine -> Tyrosine?Phe Hydroxylase

L-Tyrosine -> LDOPA?Tyrosine Hydroxylase

LDOPA -> Dopamine?Dopa Decarboxylase (requires PLP)

Dopamine -> NE?Dopamine -hydroxylase (mixed fx oxidase that needs electron donor, ascorbic acid)

NE -> E?Phenylethanol amine N-methyl Transferase (needs SAM, and adequate levels of B12 and folate)

Defective Tyrosine Hydroxylase will lead to what disease condition?Albinism

Conversion of Tyrosine to LDOPA and LDOPA to dopamine occurs where?Cytosol

-Hydroxylation occurs where?Within the vesicles

Transports catecholamines into storage vesicles?VMAT2 (12 transmembrane domains)

Concentration of catecholamines in the vesicles occurs via?ATP-dependent process linked to a proton pump (V-ATPase)

Protons are pumped into the vesicle, then exchanged for postitively-charged catecholamines via?VMAT2

Within the vesicles NT are complexed with what?ATP and acidic proteins (chromogranins)

Catecholamines are available for immediate release upon influx of what ion?Ca2+

Do catecholamines always act on nearby neurons?No, initiate responses in peripheral tissues via travel through the blood

Required for the biogenesis of the storage vesicles?Chromogranins

What is proteolytically clipped to form bioactive peptides?Chromogranins

Patients with neuroendocrine tumors such as a ____________ would have high circulating levels of chromogranins.Pheochromocytoma

Present on outer mitochondrial membrane and oxidizes the amino group to an aldehyde -> rel. ammonium ion?MAO

MAO inactivates catecholamines that are not protected by what?Storage Vesicles

Drugs that deplete storage vesicles do what?Indirectly deplete catecholamines via MAO degradation

Preferentially deaminates NE and serotonin?MAO-A

Acts on a wide spectrum of phenylethylamines?MAO-B

MAO in the liver protects against ingestion of what?Dietary Biogenic Amines (tyramine found in cheese)

Tranfers methyl from SAM to catecholamine and is works on a broad spectrum of catechols that diffused away?COMT

COMT is dependent on?B12 and folate

Cerebrospinal HVA is an indicator of ________ degradation?Dopamine

Cerebrospinal HVA would be increased/decreased in a patient with Parkinson's?Decreased

Tyrosine Hydroxylase is inhibited by what?Free cytosolic catecholamines that compete for binding sites on the enzyme for pterin cofactor (BH4)

Depolarization of the nerve terminal activates what enzyme?Tyrosine Hydroxylase

The kinases that are also activated make the enzyme more sensitive to BH4, and what?End product inhibition

Long-term regulatory process involves increased gene transcription via phosphylation of what?CREB

Which enzyme is unaffected by the increased gene transcription of enzymes for NE/E synthesis?Dopamine Decarboxylase

Degradation product of Tyrosine that can lead to palpitations, nausea, vomitting, and elevated BP?Tyramine

Where does tyramine bind?NE receptors

What is tyramine inactivated by?MAO-A

Patients taking what medication should avoid any foods containing tyramine?MAOIs

Pheochromocytoma will cause elevated levels of catecholamines in blood and?Urine

1 and 2adrenergic receptor antagonist that blocks pharmacologic effect of the elevated catecholamines? Phenoxybenzamine

Tryptophan -> 5-hydroxytryptophan?Tryptophan Hydroxylase

5-hydroxytryptophan -> Serotonin?PLP + Dopa Decarboxylase

Inactivates Serotonin?MAO

Melatonin is produced from?Tryptophan

Melatonin is made in what gland?Pineal Gland

What is melatonin synthesis linked to?Light/Dark Cycle (increases in the dark)

MAO-A selective irreversible inhibitor?Clorgyline

MAO-B selective irreversible inhibitor?Deprenyl

Parkinson's is caused by a lack of what?Dopamine

What can also be used to treat Parkinson's?Deprenyl

Third Generation MAOI?Reversible, Moclobemide

Because it's reversible, Moclobemide allows tyramine to be able to displace the drug from MAO leads to?No Cheese Effect

Family of bone marrow-derived secretory cells that store and release high concentrations of histamine?Mast Cells

They are prevelant where?In the thalamus, hypothalamus, dura mater, leptomeninges and choroid process

Histadine -> Histamine?Histidine Decarboxylase + PLP

Histamine can activate both?PreS and PostS receptors

Histamine does not appear to be ________ in the preS terminal to any great extent?Recycled

What cells have a high affinity uptake system for histamine - may be the major site of degredation?Astrocytes

First step in Histamine inactivation?Methylation via histamine methyltransferase

Second step in histamine inactivation?Oxidation via MAO-B

Low serotonin levels cause what?Increased Appetite and Decreased Mood (Depression)

Acted as an SSRI but also increased the secretion of serotonin -> elevated levels of this compound in the synapse?Redux

1st, 2nd, and 3rd Generation Antidepressants were called?MAOIs, Tricyclics, and SSRIs

Histamine released from mast cells causes?Vasodilation and Increased Permeability of Blood Vessels

Histamine released in the lungs causes?Airways to constrict in an attempt to reduce the intake of allergic material

Histamine is an __________ NT?Excitatory

Acetyl CoA + Choline -> ACH?ChAT (in the preS terminal)

Choline is taken up from blood and cleft with what affinity, respectively?Low and High

Choline is derived from hydrolysis of?Phosphatidylcholine and Sphingomyelin

Route for choline synthesis?Add 3 methyl from SAM to ethanolamine end of phosphatidyethanolamine -> phosphatidylcholine -> hydrolyzed to choline

Conversion of the following pathway is dependent upon?B12 and folate

Acetyl group comes from?Glucose -> Pyruvate and decarboxylation of Pyruvate -> Acetyl CoA

Where is pyruvate dehydrogenase found?ONLY in Mitochondria

Serine esterase that forms a covalent bond with acetyl groups, inactivating ACH?AChE

Sarin Gas is a neurotoxin that uses AChE

Excitatory NT, made de novo from glucose, does not cross the BBB, and synthesized from -keto-glutarate?Glutamate

Two routes to make Glutamate?1. Glutamate Dehydrogenase (reduces -ketoglutarate -> glutamate) - incorporates free ammonia into backbone

2. Transamination reactions (AA -> -keto -> glutamate)

Glutamine is synthesized from glutamine using?Glutaminase

Glutamine derived from?Glial Cells

Major inhibitory NT in CNS?GABA

GABA is synthesized by the?Decarboxylation of glutamate

Glutamate -> GABA?Glutamic Acid Decarboxylase

GABA is recycled in the CNS via a series of reactions called?GABA Shunt (converse GABA and Glutamate)

Uptake of GABA occurs in what cells?Glial

Process for GABA Shunt?GABA shunt in glial -> glutamate -> glutamine -> transported out of glial -> neurons -> converted back to glutamate

Serves as a transporter of glutamate b/n cells in the CNS?Glutamine

Glial cells lack what, and therefore can not make GABA?GAD

Used to increase brain ACH in patients suffering from Tardive Dyskinesia (invol. Movement face and tongue)Lecithin supplementation

Neonates have a very high demand for what?ACH

Maternal milk has high levels of what?Phosphatidycholine

Choline synthesis requires B12 and folate, so maternal requirement will be increased/decreased?Increased

Inherited pyruvate dehydrogenase deficiency, thiamine deficiency, or hypoxia leads to what?Deprives the brain of a source of acetyl CoA

Inhibits reuptake of GABA from the synapse, used to treat epilepsy (prolonged presense -> stops convulsions)?Tiagabine

Excitatory NT, synthesized from TCA intermediate Oxceloacetate?Aspartate

Major inhibitory NT in the SC?Glycine

Synthesized de novo from Serine -> Glycine via?Serine Hydroxymethyltransferase (requires Folic Acid)

Where does serine come from?The intermediate 3-phosphglycerate in the glycolytic cycle

How does glycine get terminated?High affinity uptake transporter

What is required for choline synthesis, and a lack of this may contribute to neurologic deficits?Vitamin B12

Biological messanger in a variety of physiologic respones (vasodilation, NT, ability of immune system)NO

NO is synthesized from what?Arginine

What catalyzes Arginine -> NO?NO synthase

NO synthase is tissue specific, what two forms/actions does it have?1. Macrophage Form - overproduction of NO -> cytotoxic actions on paracites/tumor cells

2. Nervous Tissue Form - Physiologic action of NO -> vasodilation and neural transmission

NO can activate what on target cells?guanylate cyclase -> cGMP

NO can activate what on smooth muscle cells?cAMP -> kinases -> relaxation of smooth muscle and dilation of vessels

Stimulates penile erection by acting as a NT -> stimulate smooth muscle relax -> corpus cavernosum to fill with blood?NO

There is evidence that NO may act as a _______ _______, stimulating NT release from the PreS.Retrograde messenger

Brain uses approximately __% of oxygen supply of the body?20%

Anaerobic Glycolysis yeilds how many ATP?2 molecules

Complete oxidation of Glucose -> CO2 can yeild approximately how many ATP?32 molecules

Encountered in medical conditions such as insulinomas, insulin like growth factors, or chronic alcoholism?Hypoglycemia

What does the brain begin to use as glucose levels fall below 2.5 mM?TCA intermediates and glutamate - these are quickly depleted

When do ATP stores become completely depleted?Glucose level below 1 mM

What happens to the EEG as the glucose levels fall below 1 mM?EEG become isoelectric -> neuronal cell death ensues

What brain areas are notably vulnerable to hypoglycemic insult?Hippocampus and Cortical Structures

Pathophysiologic mechanism for neuronal cell death in hypoglycemia?Glutamate Excitotoxicity

Failure of what results in the build up of glutamate in the cleft and overstimulation of the PostS receptors?Energy dependent reuptake pumps

Prolonged Glutamate receptor stimulation yeilds what?Open receptor ion channel -> influx of lethal levels of Ca2+ -> cytotoxic intracellular pathways in the postS neuron

Mild hypoxia results in severe congnitive dysfunction, due to what?Impaired NT synthesis

In mild hypoxia, what happens to cerebral blood flow?Increases to deliver more 02

In mild hypoxia, what happens to anaerobic glycolysis?Increases -> more ATP -> also increased lactate production and fall in pH

Inhibition of what (highly sensative to hypoxia) results in diminshed acetylcholine synthesis?Pyruvate dehydrogenase

In hypoxia, why are glutamate and GABA levels decreased?elevated NADH levels -> inhibit TCA (O2 unavailable to accept electrons from e transport chain)

Degradative pathway of the branched AA -> succinyl CoA to the TCA uses what?B12 (not folate) and is catalyzed by methylmalonyl CoA mutase

BBB restricts entry of what type of lipids?Non-essential FA

Which lipids are the exception due their essential nature?Linoleic and Linolenic Acid

Is important in the brain because the brain contains very-long chain FA and phytanic acid?Peroxisomal FA oxidation

Disorder that effects peroxisome biogenesis (unable to metabolize branched chain and VL chain FA)?Refsum Disease

PNS cells that make the myelin sheath?Shwann Cells

Schwann cell wraps itself around the axon multiple times to create what?Multilayered sheath of membrane

CNS cells that myelinate multiple axons?Oligodendrocytes

Extends this process that wraps around the axons of many neurons?Oligodendrocytes

Axons in the PNS are surround by what?The entire schwann cell

Constitute approximately 16% of total myelin lipid and are completely absent from other cell type memb. Lipids?Cerebrosides

Predominant cerebroside?Galactosylcerebroside

In the CNS, which two proteins constitute 60-80% of the total proteins? PLP and MBPs - both soluble in water and attracted to the membrane

In the PNS, the major myelin protein is what?Po, plays similar role in maintaining myelin structure as PLP does in the CNS

Where is the incidence of MS completely nil?At the equator

Primary injury to the CNS in MS is loss of what in the white matter?Myelin

What does the disease stimulate to go into remission?Oligodendrocytes

Inherited mutations in Po (PNS) leads to a version of what disease?Charcot-Marie-Tooth polyneuropathy syndrome - Autosomal Dominant

Mutations in PLP lead to what disease process?Pelizaeus-Merbacher Disease and X-Linked spastic paraplegia type 2 disease

Altered function of Po or PLP leads to what?Demyelination and its subsequent manifestations