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Cell Bio Exam 2 Outline: Lectures 17-25 Lecture 17: Anterior Pituitary – GH & Prolactin GH (Somatotropin) o 2 types of receptors on a cell make it well controlled GHRH: Gs stimulates From nucleus arcuate GHIH: GI inhibits From periventricular nucleus o General Info: It is a stress hormone that peaks when you sleep, are fasting, stressed, or during strenuous exercise Has pulses & is episodic GH is profoundly anabolic (building m.) & partially diabetogenic (decreases glucose uptake by liver & partially desensitizes glucose receptors) Structure of GH is similar to prolactin, hPL, plactenal GH variant Increase in prolactin, can have GH effects o Mechanism: Effects primarily to liver IGF-1 IGF-1 (peptide hormone) has a carrier (IGF-BP) Action of IGF-1: carries out the actions of GH IGF-1 can also be called somatomedian b/c mediates actions of GH IGF-1 is stimulated stimulates somatostatin GHIH 00> modulate GH secretion Effects mediated through binding to a plasma membrane receptor, JAK-STAT pathway o Actions of GH: Increase height in kids Increase Ca++ retention, strengthens & increases mineralization of bone Increases m. mass through sarcomere hyperplasia Promotes lipolysis and increases lean body mass Increases protein synthesis Stimulates growth of all internal organs (except brain) Role in homeostasis Reduces liver uptake of glucose! Promotes gluconeogenesis in liver o Q. What would happen if GH excess? Insulin Resistance o GH Excess Acromegaly if after puberty Anterior pituitary adenoma or prolactinoma on CT/MRI Visual field defects Prominent supraorbital ridge Cardiac hypertrophy Abnormal glucose tolerance test! Spade shaped hands and feet Txt: w/somatostatin analogs o GH Deficiency Africa pygmies (probably iodine def.) Levi-Lorain dwarfs (low IGF-1) Dwarfism Panhypopituitarism o Restricted release of all hypothalamic/pituitary hormones b/c constricted vasculature of hypothalamic/pituitary axis ACTH low = Cortisol low FSH/LH low If you lack GH small stature w/normal proportions vs. TH defect w/more overweight b/c decreased BMR o GH Secretion Promoted By: Low glucose Low FFA’s Increased arginine (w/infusions) Stressful stimuli Exercise Androgens/estrogens Alpha-andrenergic agonists o GH Inhibited By: Glucagon Increase in glucose FFA’s Aging Obesity Sustained increase in cortisol Prolactin o General Info: Produced by anterior pituitary Circulates unbound in blood Tonically inhibited by dopamine Short half-life GH can cross-react with prolactin hormone receptors o PH stimulated by: Estrogen, pregnancy Sleep Stress Pt’s w/increased TRH can have increased PH b/c TRH stimulates anterior pituitary o PH decreased by: Dopamine! Bromocriptine (dopamine agonist) Somatostatin Prolactin via negative feedback o Actions: Mammogenesis Lactogenesis Galactopoeisis Prolactin decreases 8-10 weeks post-delivery o Prolactin Excess: Causes: hypothalamic destruction or prolactinoma Failure of ovulate & amenorrhea b/c inhibits GnRH secretion Can have issues w/fertility w/excess Can txt w/bromocriptine (which is a dopamine agonist to tonically inhibit) Cell Bio Lecture 18: Posterior Pituitary – Oxytocin & ADH Oxytocin & ADH have overlapping receptors Both made in paraventricular & supraoptic nuclei of hypothalamus o Transported & stored in posterior pituitary Q. An 8 yo male is treated w/radiation and has complete loss of pituitary fxn, what would happen? Absent sexual maturation ADH o Supraoptic nuclei is where it is made o Can be taken nasally, if needed b/c it is only 10 AA long o Stimulated By: Osmoreceptors (stronger stimulation) Normal plasma osmolarity: 280-284 mOsm At 284 mOsm, ADH begins to be produced to start & reabsorb water so no dehydration At 295 mOsm, thirst is stimulated (1-2% above normal) Angiotensin II, which acts on osmoreceptors Baroreceptors 5-10% drop in blood volume (ECF), ADH starts to be produced Postural changes via barorecetors Stress via endogenous opioids o Inhibited By: Alcohol ANP ANP is made & secreted by cardiac atrial m. cells in response to increased central venous pressure or increase in plasma Na+ Increase GFR (opposite of ADH) Decreases Na+ & water reabsorption all along nephron polyuria o Actions: Water retention Acts on kidney to cause decrease in urine flow & increase in urine concentration Binds to receptor V2 Activates GS increase cAMP activates protein kinase A phosphorylates aquaporin channels at lumen of distal convoluted tubule allow water to flow into cell to increase water retention Constriction of smooth m. via V1 receptor IP3/Ca++ mechanism Mesenteric a. o Mechanism: A lot of free water is re-uptaken urine will be concentrated tubular fluid will have higher fluid osmolarity than plasma fluid TF can reach 1200 mOsm Increase water intake = TF osmolarity will be very dilute & plasma osmolarity will be around normal 280-284 mOsm o Syndrome of Inappropriate ADH (SIADH) Plasma osmolarity of 260-270 mOsm Urine osmolarity of 550 mOsm concentrating the urine Dx: ADH related peptide tumor (lung cancer) Shouldn’t be concentrating the urine w/low plasma osmolarity of only 270 mOsm Low BUN, albumin No edema or increase in total body water o Other Actions of ADH Increases mesangial cell contraction Lowers filtration coefficient of glomerular membrane & thus decreases GFR & decreases amount filtered by kidney In anterior pituitary (via V1 receptor –IP3), ADH can increase ACTH secretion Cortisol increased o Q. Why does alcohol dehydrate you? Blocks ADH release o Disturbances in ADH Regulating Water Balance Central diabetes insipidus or Neurogenic DI Lack ADH secretion b/c defect in hypothalamus Can replace ADH to txt Dx: o Higher than plasma 290 mOsm o Lower urine osmolarity (not concentrating the urine) o Water restriction makes WORSE Nephrogenic DI Resistance to actions of ADH CAN’T replace ADH Psychogenic DI (primary polydipsia) Compulsive water drinker Low plasma & urine osmolarity Water restriction = txt Oxytocin o General Info: Oxytocin & ADH have some overlap w/biologic activity Only hormone w/true + feedback o Mechanism: Stimulates contraction of uterine myometrium Release of OT is a neurohormonal reflex initiated by stretch of the cervix Natural labor inducer = UNKNOWN OT receptors expressed toward end of pregnancy, so if Ptocin is given during 5 mo of pregnancy, no contractions will occur Causes contraction of breast milk let down Doesn’t produce milk! Cell Bio Lecture 19 and 20: Adrenal Cortex Secretes “GFR” or “the deeper you go, the sweeter it gets” o Glomerulosa aldosterone (mineralcorticoids) Aldosterons retains Na+ ALWAYS NECESSARY FOR LIFE W/out aldosterone, loss Na+, retain K+ (hyperkalemia heart problems) o Fasiculata cortisol (glucocorticoids) Cortisol regulates glucose Needed for stress o Reticularis DHEA (androgens) DHEA regulates libido Not necessary for life, weak androgens All steroid hormones made from cholesterol o CYP11A1 is enzyme that cleaves side chain Also called: Cholesterol side chain cleavage Cholesterol desmolase P450ssc This is the rate limiting step in hormone biosynthesis Cholesterol Pregnenolone Pregnenolone doesn’t cause physiological change yet b/c hasn’t bound to a receptor o General Info: Cortisol is negative feedback for ACTH production ACTH induces cholesterol desomolase ***the rate-limiting step in hormone production W/out cortisol, the other hormones will be produced in excess Steroids are synthesized de novo – never stored When steroids are bound, they have a longer half-life 17-hydroxylase not in glomerulsoa layer, so only fasiculata & reticularis layers can make cortisol STAR transports cholesterol into mitochondria ACTH activates STAR Activities of Steroids o Mineralocorticoids Aldosterone = most potent Deoxycorticosterone w/1/30 the activity of aldosterone Corticosterone w/slight activity 9 alpha-flourcortisol = synthetic & MORE POTENT Cortisol = slight mineralcorticoid activity o Glucocorticoids Cortsiol = most potent Corticosterone = slight activity Cortisone = nearly as potent as cortisol Prednisone = 4x as potent Methylprednisone = 5x Dexamethasone = 30x Aldosterone o Target: Kidney (same target as ADH) cortical collecting tubules/distal tubules o Increase in ECF volume increase in BP o When Na+ is reabsorbed, it is partially exchanged for K+ and H+ o Increased expression of Na/K ATPase pump on serosal (plasma) membrane o Fine tuning of Na+ for body osmolarity o Lack of Mineralcorticoids Salt wasting hypotension Hyperkalemia (K+ retention) Metabolic acidosis (H+ not excreted in urine) o Excess Mineralcorticoids Salt retention hypertension Hypokalemia Metabolic alkalosis (H+ is excreted in urine) o Actions of Aldosterone Increase renal Na+ reabsorption in principal cells in distal tubule & CCD Increase renal K+ secretion Increase H+ secretion in intercalated cells (prevent acidosis) o W/elevated aldosterone, aldosterone escape will occur & eventually lead to normal ECV & thus normal mean arterial pressure Elevated aldosterone long-term However, K+ levels will continue to drop, and become very low o Aldosterone levels increase w/: Angiotensin II (renin stimulated) Increase in plasma K+ Increase in ACTH o How Renin works to stimulate Aldosterone Low pressure or low Na+ renin cleave angiotensinogen to angiotensin I angiotensin I to angiotensin II via ACE in lungs angiotensin II binds receptors and induces P450ssc (cholesterol desmolase) & aldosterone synthase in glomerulosa Angiotensin II also acts in hypothalamus to increase thirst and AVP (vasopressin/ADH) Mesangial cells also contract b/c of Ag II o Mechanism of Aldosterone Bind receptor induce Na/K ATPase transporter more K+ in the cell K+ to the nephron K+ excreted Also allows for Na/H exchanger to excrete H+ in urine to regulate and prevent metabolic acidosis o Counter-Regulatory Hormone = ANP Hypervolemia sensed in atrium of heart released ANP ANP binds receptor in zona glomerulosa decrease aldosterone production ANP can also bind receptors in afferent arterioles in kidney increase flow & GFR decrease reabsorption of Na+ and thus water Hypervolemia also sensed in juxaglomerular apparatus to decrease renin decrease angiotensin II down regulating aldosterone Mechanism of Steroid Formation Cholesterol Cholesterol desmolase 17a-hydroxylase 17hydroxyprenenolone pregnenolone 3Bhydroxysteroid dehydrogenase 17,20-lyase 17androgesterodione hydroxyprogesterone progesterone 21B-hydroxylase 11deoxycorticosterone 11-deoxycortisol 11B-hydroxylase Aldosterone synthase aldosterone DHEA 3B-hyroxysteroid dehydrogenase 17a-hydroxylase corticosterone 17,20-lyase Cortisol Disorder: Addison’s Disease (primary adrenal insufficiency) Cushing’s Syndrome (primary adrenal hyperplasia) Cushing’s Disease AP-problem-ACTH (secondary hypercortisolism) Conn’s Syndrome Aldosterone tumor (primary adrenal hyperaldosteronism) 21B OHase defect adrenogenital syndrome (90% will have this defect) Feature: Hypoglycemia, hyperkalemia, metabolic acidosis, hyperpigmentation m. wasting, female virilization (maybe), central obesity, striae, hyperglycemia, HTN ACTH Increased Decreased (pt is in cortisol excess & cortisol is negative feedback for ACTH) Increased (ACTH secreting tumor) Txt Glucocorticoids and/or mineralcorticoids Ketoconazole, Metyrapone Same as Cushing’s Syndrome, Removal of ACTH MSH will be elevated (darker tumor skin), cortisol elevated (ACTH high), hyperglycemia High Na+, HTN, hypokalemia, No affected by metabolic alkalosis (H+ increased excreted), plasma renin low b/c aldosterone plenty of aldosterone & HTN Virilization, symptoms of Increased (b/c no Replacement of glucocorticoid/mineralcorticoid cortisol) glucocorticoids & loss, Na+ loss (salt wasting) aldosterone hypotensive, K+ retention (hyperkalemia), H+ retention (metabolic acidosis). NO Cortisol hypoglycemic 11B OHase defect Symptoms of mineralcorticoid Increased Replacement of excess, glucocorticoid loss, high glucocortiocoids DHEA virilization, 11-DOC present (has some aldosterone like activity) Na+ retention (HTN), K+ excretion (hypokalemia), H+ excretion (metabolic alkalosis). NO cortisol hypoglycemia 17 OHase defect Symptoms of mineralcorticoid Increased Replacement of excess, symptoms of glucocorticoids & glucocorticoid deficiency. NO aldosterone DHEA NO VIRILIZIATION. antagonist Lots 11-DOC Na+ retention (aldosterone is (HTN), K+ excretion very high) (hypokalemia), H+ excretion (metabolic alkalosis), NO cortisol hypoglycemia Q. With 17a-hydroxylase defect would aldosterone levels be high or low? Levels of aldosterone would be low, because aldosterone synthase is regulated by angiotensin II. Angiotensin II is elevated when hypotensive & with this defect, we are HTN b/c 11-DOC is elevated which leads to elevated Na+ and thus HTN Q. Adrenal secreting tumor, remove it, and the patient dies 4 days later. What happened? Removed all the aldosterone (maintains Na+ concentration & secretes K+). Patient died of hyponatremia or hyperkalemia Q. 12 yo boy w/BP 160/98, low serum K+, pH 7.67 & eats licorice constantly. Can act on kidney to increase effects of MC activity and aldosterone like effects 3B-hydroxysteroid dehydrogenase defect Defect will not be compatible w/life Partial defect = won’t produce aldosterone or cortisol When DHEA is elevated, so will 17-ketone 19-carbon steroids in urine Regulation of ACTH Biosynthesis o Cortisol peaks 8 am, ACTH peaks at 7-8 am circadian o CRH = most important mediator of ACTH produced o Stress induces cortisol Cortisol Regulation o CTH induced by: CRH Circadian rhythm Stress o Cortisol is negative feedback to ACTH Dexamethasone Suppression Test o Use: Determine defect w/elevated cortisol o ACTH should go down if given dexamethasone o Low-dose overnight method, measure at 8 am If ACTH is suppressed, we know feedback is working If ACTH is not suppressed, do high dose method o High-dose overnight method If have higher set point of ACTH, the high-dose method should cause suppression of ACTH If ACTH is no suppressed with this method, then ACTH secreting tumor POMC o Prohormone of ACTH along w/other products o Adrenal insufficiency, not producing cortisol, ACTH elevated, POMC also elevated o POMC is also a prohormone to melanocyte stimulating hormone (MSH) darker skin Biological Actions of Cortisol (Many) o Anti-insulin (diabetogenic) Increase in serum glucose o Cortisol permits maximum epinephrine & stimulation of lipolysis (mostly in extremities) o Reduce bone & connective tissue by inhibiting fibroblast proliferation & collagen formation Cortisol decreases Ca++ reabsorption & intestinal Ca++ absorption Can lead to osteoporosis w/excess o Vascular system – maintain BP: Increase myocardial performance Decrease production of vasodilator prostaglandins o CNS effect – decrease REM sleep, can cause insomnia o Fetal development facilitated by cortisol Produce lung surfactant o Inflammatory & immune responses profoundly influenced by cortisol Cell Bio Lecture 21 & 22: Adrenal Medulla o Adrenal Medulla o Blood flows from capsule to medulla and along the way picks up steroid hormones o Fxn cells: chromaffin/pheochromocytes Loaded w/epinephrine, catecholamines o Similar to postganglionic sympathetic neuron “fight or flight” o If you lost your medulla, no real life-threatening effects o Cortisol is 100x higher in medulla Important b/cortisol induces PMNT which converts norepi to epinephrine 80% epi & 20% norepi o Secretion & Circulating Catecholamine Levels o Secretion increases by “emergency” conditions: Hypoglycemia Hypovolemia Hypotension Stress or pain o Rapid (epi) o Cortisol elevated 30-60 min later o 4 stress hormones: GH, cortisol, epi, glucagon o Actions of Catecholamine o β1: Epinephrine > Norepinephrine Increase cardiac contractility (β1) Increase heart rate (β1) o β2: only Epinephrine Increase m. relaxation (β2) Airway smooth muscle Vascular smooth muscle Uterine smooth muscle Increase arteriolar dilation: decrease BP (β2) o α: Norepinephrine > Epinephrine Increase gluconeogenesis o α1 receptors: Vascular & other smooth m. contraction Norepi & epi bind α1 receptors o α2 receptors: Inhibitory, act via inhibitory G-protein decrease cAMP (opposite effect from β receptors on intracellular cAMP) Norepi & epi bind well to α2 o Heart Epinephrine effects on heart Epi alone lowers total peripheral resistance via vasodilatory effects Stimulates HR via β1 β2 binding of epi will cause vasodilation, keeping HR pumping Increases BP Increases CO Norepinephrine effects on heart Norepi increases total peripheral resistance via α1 causing reflex bradycardia Decreases HR b/c only acts through α1 and β1 Decreased CO Increased BP o Overall Effects of Norepi/Epi Insulin resistance, increasing plasma glucose to supply CNS & for alternate fuels Still have glucose to m. b/c m. cells are insulin independent o Overall Actions of Norepi/Epi BMR can increase 7-15% w/epi or Norepi Epi stimulates lipolysis via β-activation Increase renin release from kidney Increase TH secretion & conversion of T4 T3 Increase β-receptor production, particularly heart Greater uterine contractions o General Info: o Epi contributes to glucose homeostastis, but is only critical when glucagon absent o Epi increases by: standing up, exercise, hypoglycemia, smoking o Most circulating Norepi is derived from “escaped” synaptic NE, NOT MEDULLA o Half life is very short (1-3 min) o Most metabolized via COMT & combo of monoamine oxidase & aldehyde oxidase o Disorders: o Neuroblastoma = MOST COMMON EXTRACRANIAL SOLID CANCER IN KIDS < 2 yo Neuroendocrine tumor Most frequently originates in adrenal glands o Pheochromocytoma Q. You suspect pheochromocytoma, what do you do? 24 hr UA o epi & norepi are met. Quickly & secreted in urine o VMA test and VMA ratio to metanephrines Pure VMA, look at normetephrine = norepi secreting tumor VMA ratio to metanephrines = epi secreting tumor Q. In a pheochromocytoma, if the prednominat-secreted hormone is epinephrine, the tumor is most likely where & due to what enzyme? Medulla, PMNT is elevated Clinical: hot flashes, racing heart, increase BP, adrenal mass Usually transient-except for mass o Epinephrine in Excess Increased BP, reflex slowing of HR Chronic effect: Increased BMR Weight loss Hyperglycemia Dx: NE & E at rest, VMA, metanephrine Txt: α-antangoist for BP, β-antagonist for bradycardia Definitive = surgical removal of tumor Cell Bio Lecture 23: Prostaglandins, Eicosanoids, Thromboxanes o Arachidonic acid is precursor to prostaglandins (PG), thromboxanes (TX), leukotrienes (LT) o Very short half-life o Locally acting o More potent against COX-1 than COX-2 o Sits in membrane until changed to PG, TX, LT o Corticosteroids (Cortisol, Prednisone, Hydrocortisone) inhibit phospholipase A2 The 1st step that releases arachidonic acid The anti-inflammatory effect o Thromboxanes (TXA2) o Produced by platelets (thrombocytes) o Actions: Vasoconstriction Increase platelet aggregation & clot formation o NSAIDs will block this via COX activation o Prostacyclin (PGI2) o Produced by vascular endothelial cells o Actions: Inhibit platelet aggregation Potent vasodilator used in Raynaud’s, ischemia in limb, & pulm. HTN o Low dose Aspirin will not affect, but high doses will o Leukotrienes (LT) o Produced by leukocytes (WBC) o LTB4 increases: Vascular permeability T-cell proliferation Leukocyte aggregation IFN-y IL-1 & IL-2 o LTC4, D4 increases: Bronchial constriction (asthma) Vascular permeability IFN-y o NSAIDs – can cause GI bleeds b/c inhibits COX-1 o COX-1 Produces PGE2 (vasodilatory) binds in stomach & decreases gastric acid secretion and increases gastric mucus secretion (protection) COX-1 inhibitor = more acid, less mucus, more GI bleeds o COX-2 inhibitors Reduces risk of peptic ulceration COX-2 inhibitors increases risk of atherothrombosis w/2 fold increased risk of MI Adverse effect, also possible increased risk of renal failure o Baby aspirin (acetylsalicylic acid) o Irreversibly blocks COX activation of platelet for life of platelet Cell Bio Lecture 24 & 25: Calcium Disorder PTH Serum Ca++ Serum PO4Primary Increased Increased Decreased Hyperparathyroidism Primary Decreased Decreased Increased Hypoparathyroidism (usually from thyroid removal) Renal Failure (similar to Increased Decreased Increased primary hypoparathyroidism) Secondary Increased Decreased (this is the Decreased hyperparathyroidism cause) (caused by decrease in plasma Ca++-Vit D deficiency) Secondary Decreased Increased (too much Increased Hypoparathyroidism absorption of Ca++) (increase in plasma Ca++ too much Vit D) o Vitamin D toxicity causes both elevated plasma Ca++ and elevated plasma phosphate o This is due to increased Ca++ and Vit. D shutting off PTH secretion (which normally would increased phosphate loss in urine) o Lack of Vitamin D causes rickets growth failure & limb deformities in kids o Osteomalacia (softening of bones) occurs in adults o Define: loss of mineralization of the bone matrix collagen, w/out actual loss of the matrix o Free calcium is regulated mainly by PTH which acts to raise Ca++ by both fast and slow actions o Fast actions of PTH include increased Ca++ reabsorption in the kidney, inhibition of phosphate and transfer of free calcium from the interstitial fluid surrounding the bone o Calcitonin lower plasma calcium by decreasing activity of osteoclasts o In primary parathyroidism, plasma Ca++ and phosphate change in opposite direction but they change in the same direction in secondary disorders o Main circulating form of vitamin D is 25-OH form, but actual physiologic form is 1,25 OH o Normally, vitamin D promotes bone deposition b/c it increases the plasma levels of both Ca++ and phosphate o Vitamin D deficiency is an example of a secondary hyperparathyroidism o Calcium o Plays crucial roles in m. contraction, nerve function, and blood coagulation o Normal levels: 8.5 to 10.5 mg/dl o Decreased Calcium increased neuromuscular excitability, tetany, laryngeal spasms, asphysiation o Increased Calcium decreased neuromuscular excitability, bone pain, lethargy, anorexia, muscle weakness, constipation, calcium stones (stones, bones, and groans) o Phosphate o Hyperphosphatemia leads to increased binding of free Ca and thus decreased free Ca o PTH o Negative regulator of PTH is plasma free Calcium o PTH is tonically inhibited by Calcium o Major control mechanism of calcium homeostasis o PTH secreted in response to decreased plasma Ca++ levels o Excess activity of parathyroid gland causes rapid reabsorption of calcium salts from the bones, with resultant hypercalcemia in the ECF o Hypofunction of the parathyroid gland causes hypocalcemia tetany o Acts to increase calcium reabsorption in distal tubule but decrease PO4 reabsorption in proximal tubule o Vitamin D o Activated by: Low plasma free Ca++ Low plasma PO4 High PTH Low 1,25-OH-D3 o Calcitonin o Has opposite effect of PTH o It lowers plasma calcium o Secreted from thyroid C-cells begins when plasma calcium levels are above 9.5 o Target cell of calcitonin is: osteoclast