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Describe the male hypothalamus-hypophysis gonadal axes

Leydig cells: under influence of LH; make testosterone Sertoli cells: under influence of FSH; make inhibin to negatively feedback on pituitary (to inhibit LH/FSH) also sertoli cells = support cells that hold spermatogonia at different levels of development; the basal lamina and tight junction forms the blood testis barrier Regulation/feedback inhibition: Inhibin and testosterone on pituitary to inhibit FSH and LH testosterone on hypothalamus to inhibit GnRH


Describe the female hypothalamus-hypophysis gonadal axes

Estradiol (E2) is produced by the granulosa cell of the developing follicle; E2 feedback is mainly negative but in midcycle there is a positive feedback to hypothal (+GnRH) and pituitary (+FSH and LH) which results in the LH surge that causes ovulation Progesterone is secreted by the resultant corpus luteum


Describe spatial and temporal summation

summation of EPSP and IPSP (presynaptic potentials); signal transduction that determines whether or not threshold will be met and an AP will result Spatial = multiple areas of input temporal = high frequency of PSP overlap and summate with eachother


How does adrenaline (epinephrine) stimulation glycogenolysis?

epi binds to ALPHA adrenergic receptor --> trimeric Gprotein --> phospholipase C --> PIP2 to DAG and IP3 IP3 = opens ER Ca2+ channels from reservoir and increases Ca2+ concentration; the increase in Ca2+ can complex with calmodulin and cause stimulation A). phosphorylase Kinase (stimulated glycogen phosphorylase) B). Ca2+/calmodulin dependent kinase: w/ PKC does protein phosphorylation leading to phosphorylation of transcription factors (+ or -) DAG: activates protein kinase C (PKC) to increase protein phosphorylation that leads to phosphorylation of transcription factors (+ or -) epi binding to BETA adrenergic receptor: PKA /cAMP dependent pathway = same as glucaogn (1. phosphorylase kinase 2. inhibin-1 3. inactivation of glycogen synthase 4. difunctional enzyme to decrease F26BP and stimulate gluconeogen)


Describe the effect of insulin on the liver

** glucose uptake is INDEPENDENT of insulin because the liver uses GLUT 2 transporter that is ALWAYS expressed regardless of insulin levels Stimulates: glycolysis glycogen synthesis lipogenesis (because glucose to ACoA to FA to TAG ** no storage of TAG because TAGs released as VLDL and transported from liver to adipose) uptake of aa and conversion to protein Storage of: glycogen protein **does not normally store fat/TAGs because TAGs are released in VLDL (unless a condition in which unregulated glucose conc causes unregulated lipogenesis (ie: DKA) and then fatty liver results) *ATP dependent uptake of K+ occurs in all cells w/ receptor for insulin


Describe the biochemical pathway of glucagon on the liver

IN GENERAL: glucagon binds to a plasma membrane receptor and activates a TRIMERIC G PROTEIN (specific) --> cAMP --> PKA --> phosphorylation CAUSES INCREASED GLUCONEOGEN AND DECREASED GLYCOLYSIS Details: Trimeric Gprotein: GDP is bound to the alpha-subunit on Gprotein receptor; once glucagon binds to the receptor, GDP is released and GTP binds and the alpha subunit; then alpha subunit w/GTP leaves and activates adenylyl cyclase which released cAMP and GDP (which goes back with alpha subunit to reform on the receptor) cAMP = second messenger that activates PKA active PKA causes phosphorylation of three main pathways: 1. phosphorylase kinase (active when P) 2. inhibitor-1 (active when P) 3. glycogen synthase (inactive when P) INDIRECT EFFECT OF GLUCAGON = 1 &2 1, Phosphorylase kinase: when phosphorylated by PKA is it active; it goes on to phosphorylate 'Glycogen Phosphorylase' which breaks down glycogen by phosphorylating glucose residues (glucose 1 -P removed) 2. Inhibitor-1: when phosphorylated by PKA = active; it causes inactivation of Protein Phosphatase; Normally, protein phosphatase is an inactivator of glycogen phosphorylase (stim by insulin) and causes activation of HMG-CoA reductase which catalyzes cholesterol/steroid hormone synthesis; therfore by P on hibitor-1 you activate it, and inactivate PPase and thus inhibit HMG-CoA reductase DIRECT EFFECT OF GLUCAGON: 3. Glycogen Synthanse: when phosphorylated by PKA = inactive therefore it directly promotes inhibition of glycogen formation; THUS: PKA = stimulates glycogenolysis


Describe the binding curve for a ligand/receptor

x = free L y = bound L hyperbola with "vmax"


Describe Methemoglobin Reductase

Biding of O2 to Hb can occasionally lead to reduction of O2 to O2dotminus (superoxide anion radical) and the oxidation of Fe2+ to Fe3+ resulting in the formation of metHB; metHb may release heme, which reacts with O2 and H2O2 to produce hydroxyl-radical (OHdot) MetHb reductase reduces the metHb to normal ferroHb (returns normal activity of Hb)


Describe the breakdown of Phophatidylcholine

PLA2 = phospholipase A2: cleaves acyl + 1 chain FA from phosphatidly choline cPLA2 = cytosolic PLA2: cleaves arachadonic acid for intracellular signaling sPLA2 = secretory PLA2: ubiquitous, cleaves arachadonic acid for inflammatory response PLC = phospholipase C: cleaves DAG and choline phosphate (at site 3) PLD : cleaves phosphatidic acid and choline (takes choline off phosphatidyl choline)


Describe the formation of ROS (by Fenton and Haber Weiss Reactions, etc)

1. Fenton = oxidizing power of Fe2+, Cu2+ and H2O2; Fe2+ + H202 --> Fe3+ (ferric) + OHdot + OH- 2. Haber Weiss = non-metal reduction of O2- superoxide anion (O2-) + H2O2 --> O2 + OHdot + OH- 3. metal-catalyzed Haber Weiss = redox activate metal ions catalyze H-W reaction in physiological conditions (combo of Fenton + H-W) H2O2 -->OHdot + OH- via Fe2+ -->Fe3+ then Fe3+ --> Fe2+ (regeneration) via O2- to O2 4. ROS can be produced by several enzymatic reactions: monomamine oxydase, peroxisomal FA Oxidases, xanthine oxidase


Describe the process of phototransduction

photopigments = iodopsin in cones; rhodopsin in rods In NORMAL (no light) conditions: photoreceptor is depolarizaed due to high amounts of cGMP which produces the opening of channels Na+ and Ca2+ which causes an inward current of Na+ (+charge = - current which is depolarizing) leading to depolarization and constant release of glutamate by receptor (which can bind to NMDA receptor) SO IN THE DARK, PHOTORECEPTORS ARE CONSTANTLY RELEASING GLUTAMATE IN LIGHT: activated rhodopsin (or iodopsin) cuases cis-retinAL to trans-retinAL which comes off the opsin; the structural change actives TRANSDUCIN wich activates the cGMP phosphodiesterase (PDE) which converts cGMP --> 5'GMP and inactivates (closes) the ion channel therefore HYPERPOLARIZING the cell and STOPS THE RELEASE OF GLUTAMATE Biopolar cells respond to glutatmate depending on the type of glutamate receptor they express: 1. iGluR non-NMDA receptors bipolar cells = OFF cells; they are hyperpolarized by the decrease in glutamate (by light) 2. mGluR on bipolar cells = ON cells; they are depolarized by the decrease in glutamate (by light) depolarzation = increase in the conductance SO IN THE LIGHT: bipolar cells with mGluR are depolarized due to the decrease in glutamate (opposite of iGluR non NMDA OFF bipolar cells) Bipolar cells produce graded potentials to the light stimulus but no actual AP!! BACK TO DARK: activated rhodopsin is silenced by a serine/threonine receptor kinase (RK) which prepares the rhodopsin for arrestin; arrestin binding blocks further G-protein mediated signaling.


Describe the activation of thyroid hormones

T4 = inactive but made 10x more than T3; deiodination of T4 to T3 occurs primarily in the thyroid gland and the LIVER via diodinases; T4 diodinated to T3 and rT3 in about equal amounts, but only T3 is active; Most of T4 and T3 is bound to thyroid binding globulin (TBG) and other proteins, but 0.03% T4 and 0.3 T3 are circulating and "active" T4 and T3 cross the Plasma memb via specific carriers that bind to INTRACELLULAR RECEPTORS that act as TRANSCRIPTION FACTORS


Describe the effects of GH on the: -liver -adipocytes -muscle -other

direct effect = anti-insulin indirect = via IGF-1 -liver: increased production and release of IGF-1, increased glycogen storage, increased gluconeogenesis; decreased glycolysis (all via increased stimulation of thyroid hormone production causing increased metabolism of all cells) -adipocytes decreased glucose uptake and glycolysis; increased lipolysis -muscle increased protein synthesis and increased nucleic acid synthesis, decreased glucose uptake and decreased glycolysis -other increased chondrogenesis and increased muscular and visceral growth


Describe the different enzymatic defenses against ROS:

1. Superoxide dismutase (SOD): catalyzes internal oxidation andDe reduction of O2dot- 2O2dotminus --> O2 and H2O2 2. Catalase (CAT) = catalyzes internal oxidation and reduction of H2O2 (is the most reactive enzyme in the body) O2 + H2O2 --> O2 + 2H2O 3. Glutathione Peroxidase (GPx): reduces H2O2 and lipid peroxides USING GSH AS A COSUBSTRATE; H2O2 + LOOH --> 2H2O 4. Glutathione Reductase: reduces GSH for a substrate for GPx GSSG --> 2GSH using NADPH from PP shunt 5. Methemoglobin Reductase


What are the neurotransmitters involved in the ANS?

all preganglionic = ACh release which binds to nicotinic receptor (ionotropic) on post-gang SS = NE postgang on SMC of blood vessels etc. PS = ACh postgang on muscarinic receptor (metabotropic) on glands ec. some PS also release NO postgang Motor neurons release ACh which act at distinct nicotinic receptors


Describe the effects of diabetic ketoacidosis (DKA)

DKA = due to lack of insulin which causes increased hyperglycemia (via gluconeogenesis) body is acting like it is in high glucagon: 1. increased lipolysis: = increase ketogensis = ketoenemia; ketoenemia causes 1). ketouria = osmotic diuresis (which leads to dehydration) and 2). acidosis (causes compensatory hyperventilation) 2. increased gluconeogenesis =decresed glucose uptake = hyperglycemia = glycosuria = osmotic diuresis = dehydration OVERALL: DKA CAUSES: 1. polydipsia (frequent thirst) due to severe dehydration 2. polyurea (frequent urination) due to osmotic diureses (also glucose in urine) 3. Polyphagia (frequent hunger) due to stimulation of a center in the brain and poor uptake of glucose by the brain


Describe the precursors of steroid biosynethesis:

Cholesterol to Pregnenalone (non-hormone precursor of all hromones) pregnenalone to: 1. Progesterone (to corticosterone and 17 hyrdoxy progesterone ) 2. 17-hyrdozy pregnenalone (to 17 hyrdoxy progesterone and androstenedione) Corticosterone (from progesterone) to aldosterone (C21) and cortisol (C21) 17 hyrdoxy progesterone to cortisol (C21) and androstenedione androstenedione to testosterone (C19) and estradiol (C18) testosterone to DHT and estradiol SUMMARY: corticosterone = precursor for both aldosterone and cortisol (mineral and glucocorticoids) androstenedione = precursor for both testosterone (androgen) and estrone (estrogen) Everything can be made from progesterone; everything can also be made from pregnanlone to 17 hydroxypregenalone EXCEPT mineralcorticoids (only made from progesterone)


What are the factors that affect circulating ca2+ fractions?

1. PTH increases circulating [Ca2+] and decreases [P]; in return this causes PTH release via sensing G-protein receptors in the parathyroid 2. Vitamin D (1,25 (OH2) D3) binds to a transcription factor and stimulates ACTIVE uptake of Ca2+ and Pi by a membrane pump in the epithelium of the small intestine. Passive absorption is controlled by [Ca2+] in the intestinal lumen (determined by diet) relative to the serum concentration. Excess Ca2+ is excreted in the urine and feces


Describe water reabsorption in the tubules of the nephron

PT: iso-osmotic following ions TALH: impermeable DT: Na+ reabs via aldosterone drives need for osmotic reabs of water; ADH controls DT/CD AQP2


Describe the lipid peroxidation reaction

OHdot attacks a polyunsaturated FA (PUFA) forming radial that rearranges a conjugated dienyl radical; -the radical reacts with ambient O2 to form a peroxyl radical which steals a hydrogen from a neighboring lipid, formin a lipid peroxide and starts a chain reaction: Lipid peroxide is decomposed to malondealdehyde (MDA) and 4-hydroxynonenal = 2 products that react with protein to form advanced lipoxidation end products (ALEs); ROS can also react with carbs to make advanced glycation end-products (AGEs) BASICALLY: OHdot (from fenton/HW/enzyme reactions) acts on lipids to cause mass destruction of lipid membranes and also forms malondealdehyde (MDA) and 4-hydroxynonenal wich are chemically aggressive themselves and act on other proteins to destroy them (ALEs) or ROS that act on carbs + proteins to make AGEs


Describe what counter current exchange is and how gradients are set up throughout each part of the nephron (describe in detail what happens at each part of the nephron with respect to osmolality and ions)

1. Proximal Tubule: iso-osmotic reabsorption of Na+ and water due to localization of Na/K pump only on the blood side of the tubules; urine = isotonic 2. Descending loop of Henle: osmotic removal of water (reabsorption) and addition of Na+ by passive transport (secretion) to equilibriate with ISF; urine = hypertonic 3. Ascending loop of Henle: impermeable to water, permeable to Na+ and Cl- which are reabsorbed. Result in dilution of the tubular fluid and ISF = hypotonic (what draw out water into the descending loop of H); urine = hypotonic loop of henle = counter current multiplication 4. Distal Tubule/Collecting Duct = counter current exchange: hypotonic urine enters; under the control of aldosterone via RAAS (Na+ reabsorption, K+ secretion) causes reabsorption of Na+ and therefore water must follow (via ADH and AQP2 via V2 receptor); need to maintain electroneutrality (since lumen becomes slightly negative as Na+ is being reabsorbed, K+ and H+ are secreted while Na+/H2O are reabsorbed; Result: urine = super concentrated (4x plasma osmolality)


How is the ascorbate radical regenerated?

ascorbate radical (dehydroascorbyl radical) undergoes DISMUTATION to : 1. L-ascorbate (vitamin C fully reduced) or to 2. dehydroascorbate (fully ox vitamin C) which can then be recycled to L-ascorbate (vitamin C fully reduced) VIA DEHYDROASCORBATE REDUCTASE (GSH) which uses glutathione as a co-factor in the recycling of vitamin C for the recycling of vit E to act as an anti-oxidant and prevent cell degeneration


Describe the Polyol Pathway

-activated at high glucose plasma concentrations (ie: independent of insulin as in insulin resistance) due to high Km of ALDOSE REDUCTASE which is greater than normal glucose concentrations (polyol pathway is only activated if glucose concentration is seriously increased) -contributes to the development of diabetic neuropathy in insulin-independent tissue causes: glucose --> soribital (via aldose reductase and uses NADPH) sorbital --> fructose (makes NADH) causes an increase in reducing equivalents (NADH) to mitochondrial cytochrome chain; causes increased production of reactive oxygen species (ROS) also, increase in fructose exacerbates the DM response increase in sorbital causes swelling of lens also decreased NADPH which is an anti-oxidant like molecule INHIBITORS ACT ON RATE LIMITING STEP AT ALDOSE REDUCTASE


What happens during post-absorptive metabolism (overnight fast)?

= LOW INSULIN, HIGH GLUCAGON/ADRENALINE Gluconeogenesis, glycogenolysis, and lipolysis stimulated to increase glucose: glucose is usually used by the liver as it is consumed/made, but parts of the body (RBC, brain, peripheral) depend on glucose for metabolism so the LIVER BECOMES A GLUCOSE PRODUCING ORGAN *note: in post-pranadial (after a meal) metabolism, insulin increases and glucagon decreases, and insulin acts to store glucose and metabolize it for synthesis of other macromolecules (anabolic fxn)).


What is the function of the glyoxylase system? describe it

= detox pathway of MGO Glyoxalase I: adds GSH to MGO and causes rearrangement of a non-enzymatic adduct to a THIOESTER Glyoxalase II: uses H2O to catalyze the hyrdolysis of the the thioester to form D- LACTATE and regenerate GSH PROCESS DOES NOT CONSUME GSH (unlike GPx) Note: L-Lactate comes from lactate dH but D-lactate can still go to pyruvate


Describe the relationship between hypothalamus, pituitary (ant/posterior) and what they each secrete

Hypothalamus: secretes: TRH, CRH, GnRH, GHRH = stimulates pituitary somatostatin, dopamine = inhibit pituitary Posterior pituitary = hormones are synthesized and packaged in the supraoptic and paraventricular nuclei of hypothalamus and transported via axons and then stored in the posterior pituitary hormones released = ADH, oxytocin Anterior pituitary = releasing/release inhibiting hormones are synthesized in the nuclei and transported to the median eminence where they enter a portal venous system and travel to anterior pituitary to cause release or inhibition of ant pit hormones horomones released = FSH, LH, ACTH, TSH, Prolactin, GH (somatotropin)


`Describe the effect of insulin on the skeletal muscle

glucose uptake is DEPENDENT on insulin (GLUT4 transporter) Stimulates: glycolysis glycogen synthesis uptake of aa and converstion to protein (doesn't stimulate lipogenesis because ACoA used for energy via TCA not for FA synth) Storage of: glycogen protein TAGs (some) *ATP dependent uptake of K+ occurs in all cells w/ receptor for insulin


Describe how glucagon regulates gluconeogenesis and glycolysis in the liver (including difunctional enzyme)

glucagon --> receptor --> trimeric Gprotein --> cAMP --> PKA --> 1. Phosphorylase Kinase (stim. glycogen phosphorylase) 2. Inhibitor-1 (inhibits Protein Phosphatase/HMG-CoA reductase) 3. inactivates glycogen synthase 4. phosphorylates difunctional enzyme: FBPase -2 (fructose 2,6, bisphosphatase) and PFK-2 phosphorylation = stimulation of FBPase -2 and inhibition of PFK -2; results in an decrease in the concentration of F26BP F26BP = allosteric regulator of PFK-1 and FBPase-1 so DECREASE in F26BP = stimulation of FBPase-1 and inactivation of PFK-1 therefore stimulation gluconeogenesis and inhibiting glycolysis (*insulin causes opposite effect)


Describe the glutamate receptor

glutamate = glu 1. metabotropic receptors (mGluR) 2. ionotropic receptors (iGluR) A). non-NMDA: do not bind NMDA; bind glu glu binding opens a non-selective channel that is MORE PERMEABLE to Na+ and K+ than Ca2+ causes an inward current at membrane potentials more negative than 0mV and an outward current at membrane potentials more positive than 0mV B). NMDA: bind glu and a glu analogue, N-methyl D-aspartate (NMDA); glue binds and opens a non-selective channels that are LESS PERMEABLE to Na+ than Ca2+ Have slower kinetics than non-NMDA -have binding sites for glu, gly, Mg2+ (ligand and voltage gated; all 3 necessary for receptor activation); Zn2+ (blocks channel in voltage dependent manner), a polyamine recognition site, and an antagonist binding site for PCP Ligand gated: binding of Glu required to activate the channel (and some gly binding also required) Voltage gated: at negative membrane potential, Mg2+ ions occupy the binding site causing less current to flow through the channel; as the membrane depolarizes, the Mg2+ block is removed; SO TO ACTIVATE NMDA receptors: need to first depolarize the membrane in order to remove the Mg2+ from blocking the channels; then you increase the sensitivity of gly/glu binding; note zinc also blocks the channel


Describe the role of bicarb as a buffer

blood pH is proportional to the ratio of plasma [HCO3-] to the partial pressure of CO2 (pCO2) pCO2 depends on the respiratory rate [HCO3] = metabolic component; depends on the amount of non-volatile acids produced in the tissues metabolic (HCO3 low ) vs respiratory (H+ high) = acidosis metabolic (HCO3 high) vs respiratory (H+ low) = alkalosis metabolic deficiencies are fixed by changes in respiratory rate (done quickly) while respiratory deficiencies are fixed by changes in the kidney metabolism overtime (take longer response)