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Endocrinology Sg

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I. What is endocrinology? * The study of hormones chemical messangers * Nucleus collectiom of cell bodies of neurons of CNS * Ganglia collection of cell bodies of PNS II. Neurotransmitters vs. hormones * Neurotransmitters: * released into synapses (aka synaptic cleft) via exocytosis * secreted from the secreting cell to the target * affinity of neurotransmitter receptor binding lower because more neurotransmitter concentrated in synapses * Hormones: * released into circulation by exocytosis hormones diluted in blood * received by distant target cell (endocrine) * affinity of hormone receptor binding higher affinity for hormone because hormone in diluted in blood III. 3 types of hormone signals: * endocrine signalclassic hormone; stimulated far away via blood * paracrine signalstimulates adjacent target cell (para= beside) * autocrine signal stimulates itself (auto= self) IV. Chemical classes of hormones: * Proteins multiple peptides/ long polypeptide chain
- ex: glucagon/ insulin * Steroids made of cholesterol * ex: testosterone/ estrogen * cholesterol:

* 20-22 desmolase acts on cholesterol to make a 21 carbon molecule called pregnenolane (aka P450SCC- Side Chain clearing) * 20-22 desmolase is the 1st enzyme to modify cholesterol during steroidegenisis (synthesis of a seriod) * Peptides short chain of amino acids via peptide bonds * ex: TRH- tripepide/ Thyroxine Releasing Hormone/ oT- nonapeptide * amino acid:

* Tyrosine: Tyr used to make T3 and T4 (metabolic hormones)

* Cystine: Cys sulfer containing; used to synthesize oxytocin (nonapeptide with disulfide bond b/t C #1 and #6)

disulfide bond formed via dehydrogenation of 2 Cys * Glycoprotein a mix b/t carb. (sugar) and protein (glyco= sugar) * Ex: TSH Thyroid Stimulating Hormone/ FSH Follicle Stimulating Hormone * Biogenic amines (monoamines) * derived from amino acids * ex: 1) catecholamines derived from Tyrosine (Tyr)

* all catechol amines have catechol ring (shown above) * dopamine, epinephrine, and norepinephrine are all catecholamines that contain 1 amine group (monoamine)

* V.

* ex: 2) Thyroid Hormones * T3: Thiododthyronine * T3: Tetraiodothryonine * Metabolic hormones * Monoamines * Derived from tyrosine VI. Regulation of Hormone Secretion: * Negative Feedback Inhibition * hormone regulates its own secretion if in excess * ex: Thyroid hormones Parvocellular/ parvicellular neurons of hypothalamus
Parvocellular/ parvicellular neurons of hypothalamus

Secretes TRH- Thyroid Releasing Hormone

Secretes TRH- Thyroid Releasing Hormone

Thyrotropes of Anterior Pituitary are target cells for TRH
Thyrotropes of Anterior Pituitary are target cells for TRH

Secretes TSH- Thyroid Stimulating Hormone

Secretes TSH- Thyroid Stimulating Hormone

Follicular Cells of Thyroid gland are target cells for TSH
Follicular Cells of Thyroid gland are target cells for TSH

Secretes T3 and T4; in excess, T3 and T4 will feedback and inhibit Thyrotropes and parvocellular neurons

Secretes T3 and T4; in excess, T3 and T4 will feedback and inhibit Thyrotropes and parvocellular neurons

* Be able to draw this with anatomical features * Positive Feedback Loop * hormone secretion stimulates to make more hormone * ex: 1) oxytocin released during parturition (giving birth) Magnocellular neurons of hypothalamus- reaches all the way to posterior pituitary
Magnocellular neurons of hypothalamus- reaches all the way to posterior pituitary

Secretes oxytocin (OT)

Secretes oxytocin (OT)

Posterior Pituitary
Posterior Pituitary

Releases OT to uterus and induces contraction

Releases OT to uterus and induces contraction

Head of baby pushes against cervix; nerve impulse travels via sensory or afferent neurons

Head of baby pushes against cervix; nerve impulse travels via sensory or afferent neurons

* ex: 2) lactation Mechanical stimulation
Mechanical stimulation

Nerve impulses travel via sensory neurons

Nerve impulses travel via sensory neurons

Magnocellular neurons of hypothalamus
Magnocellular neurons of hypothalamus

Releases OT from posterior pituitary

Releases OT from posterior pituitary

Induces milk ejection (not production)

Induces milk ejection (not production)

* Be able to draw with anatomical features * Substrate (target for hormone) regulation * ex: insulin regulates glucose, so glucose level regulates production of insulin * glucose level after a meal goes up (normal range 80-110mg/100mL) * stimulates insulin secretion by beta cells of pancreatic islets * Ion Regulated Hormonal Secretion * ex: Calcium- Ion needs to be regulated to control muscle contraction Ca ++ sensor on chief cells of parathyroid gland (4 loops on posterior thyroid); relaxed conformation if hypocalcemic and tight conformation if hypercalcemic
Ca ++ sensor on chief cells of parathyroid gland (4 loops on posterior thyroid); relaxed conformation if hypocalcemic and tight conformation if hypercalcemic

Secretes PTH- Parathyroid Hormone if hypocalcemic

Secretes PTH- Parathyroid Hormone if hypocalcemic

Increases Ca++ level by targeting different types of cells (cells of distal convoluted tubules in kidneys which reabsorb Ca++ into blood
Increases Ca++ level by targeting different types of cells (cells of distal convoluted tubules in kidneys which reabsorb Ca++ into blood

* know how to draw with detailed information about Ca++ sensor given later * normal Ca range: 8.5 to 10.5 mg/dL VII. Different Types of Hormone Receptors: * Receptors bound to plasma membrane - ex: GPCR- G Protein Couple Receptor * Cytosolic Receptor * receptor in cytoplasm of cell * ex: steroid hormones are lypophilic and can pass through plasma membrane * Nuclear Receptors * Receptors in nucleus * Ex: Thyroid Hormone Receptors; T3 can pass through plasma membrane and nuclear envelope; T3 receptor bound to DNA and acts as transcription factor VIII. GPCR * Know how to draw * Once a hormone binds to receptor it activates - A G protein assumes a conformation in which GTP binds to G protein rather than to GDP (activated) * G protein is hetero trimetic protein * alpha, beta, and gamma subunits * alpha subunit released when G protein activates and beta- gamma units stay together * 3 main types of alpha subunits * Gs activates enzyme Adenylate Cyclase (plasma membrane) * Ex: * beta andrenergic receptors * TSH receptor * T3 receptor (nuclear) * NPR (Natriuretic Peptide Receptors) Guanylyl Cyclase * Gq activates Phospholypase C (plasma membrane) * Ex: * Alpha 1 adrenergic receptor * V1R (Vasopresion Type 1 Receptor) * Gi inhibits Adenylate Cyclase * Ex: * Aplha 2 adrenergic receptor (GABA, SS receptor, smooth muscle receptor) * Gs ATP : Adenosine Triphophate

ATP : Adenosine Triphophate

AC: Adenylate Cyclase
AC: Adenylate Cyclase

cAMP: cyclic Adenosine Monophosphate
+ PPi; second messengers cAMP: cyclic Adenosine Monophosphate
+ PPi; second messengers

* ATP * Nucleotide * Nitrogenous base Adenine * Sugar ribose * 3 phosphate AC
AC

*

* cAMP

* example of hormone that uses Gs: TSH (Thyroid Stimulating Hormone) * How TSH works: * Released by Thyrotrope of ant. Pituitary * Follicle of thyroid gland is target cell of TSH

Epical membrane
Epical membrane

Lumen
Lumen

basolateral membrane basolateral membrane

* Know how to draw process of TSH traveling from thylotrope via blood vessel, binding to receptor, activating Gs, ATP cAMP+ PPi via AC, and follicle releasing T3 and T4 (mostly T4) * cAMP goes on to act as a 3rd messanger to activate PKA * Gq PIP2: Phosphotidyl Inosital Biphosphate (phospholipid)

PIP2: Phosphotidyl Inosital Biphosphate (phospholipid)

PLC: Phospolypase C
PLC: Phospolypase C

DAG: Diacyl Glycerol
+ IP3: Inositol Triphospate second messangers
DAG: Diacyl Glycerol
+ IP3: Inositol Triphospate second messangers

* PIP2 Glycerol + fatty acid PIP2

H2O
H2O

This is arachidonic acid- 20C polyunsat. Fatty acid
This is arachidonic acid- 20C polyunsat. Fatty acid

PLC
PLC
3
3
1
1

4
4
1
1
Biphosphate
Biphosphate
Phosphodityl
Phosphodityl
3
3

Inosital
Inosital

* IP3 * Polar head P
P
P
P

P
P

* Role of IP3 * Diffuses into the ER via ligand-gated Ca++ channels which releases Ca++ into cell * Also opens ligand- gated ca++ ion channel in membrane to bring Ca++ into cell * Ca++ binds to calamadulin and acts as 3rd messenger * DAG * Nonpolar tail OHH
OHH

* Stays in plasma membrane to activate protein kinase C (PKC) that activates many enzymatic rxns **Be able to draw entire process according to where it occurs in the cell * Example of hormone that uses Gq: TRH (Thurotropin Releasing Hormone) * How TRH works: * Source of TRH parvicellular neurons of hypothalamus * Target cell of TRH thyrotropes of ant. Pituitary * Be able to draw entire process of TRH binding to G protein receptor, activating Gq, PLC IP3/ DAG, and releasing TSH * Know what IP3 and DAG go on to do * Know Ca++ acts as 3rd messanger * V1R (Vasopresion type 1 receptor) * Receptor for AVP (Argenine Vasopression) aka ADH (Anti-diuretic hormome) * Know how to draw * Like oT, AVP is released from magnocellular neurons of hypothalamus and stores in posterior pituitary * oT and AVP use hypothalamo hypophyseal tract to deliver oT and AVP to post. Pit. * Location: smooth muscle cells of kidney arterioles * Uses Gq GCPR to make smooth muscle cell contract bc Ca2+ binds to camodulin * V2R (Vasopression Type 2 Receptor) * Ligand: AVP/ ADH * Uses Gs GPCR * Location: cells of collecting duct plasma membrane * Causes conservation of H2O * Gi * Example of hormone that uses Gi: SS (Somatostatin) * How SS works: * Released by hypothalamus * Reaches somatotropes of ant. Pituitary * Know how to draw SS biding to receptor. Which activates Gi, which inhibits AC so ATP does not cAMP+ PPi * Because no cAMP is formed, no Growth Hormones (GH) will be released * Hyper-secretion of GH before puberty can lead to Gigantism (very tall) * Hypo- secretion of GH before puberty can lead to Dwarfism * Tumor in somatotroph of ant. Pituitary can lead to hyper- secretion of GH during adulthood Acromegaly (thick bones) IX. Tyrosine Kinase Receptors * One transmembrane domain receptors (monomer or diamer) * Ex: * Insulin receptor * IGF-1 receptor (insulin growth factor 1) * EGF receptor * Use IRS (insulin receptor substrate) called SOS (sons of sevenless) as transducer * Tyr subunits auto-phosphorylated when insulin binds X. Serine/ Threonine Kinase receptors * Ex: - BMP (Bone Morphogenetic Proteins) receptor and other TGF beta receptors (Transforming growth factor) * Smads used as transducer * proteins homologous to “sma’ and “MAD” * sma C. Elegans * mad (mothers against decupentagenic) of Drosophilia * one transmembrane receptor * BMP binds and receptor auto-phosphorylated XI. Cytokine receptors * GH (Growth Hormones) * PRL (Prolactin) * Leptin receptors * JAKs (Janus Kiases) and STATs (Signal transducers and Activators of transcription) as transducers XII. Dissociation Curve of Hormone/ Receptor Interaction

R0= total # receptors bound; point where receptors reach saturation
R0= total # receptors bound; point where receptors reach saturation

½ R0
½ R0

[HR]
[HR]

KD= dissociation constant
KD= dissociation constant

[H]
[H]

* The lower the KD value, the higher the hormone’s affinity for the receptor * Know how to draw and compare the affinity of 2 hormones * You need a wide range of [H] so you can reach saturation in lab, so instead we transfer the hyperbolic relationship to linear * Must reach saturation in order to determine R0 * Scatchard Plot * [HR]/[H] vs. [HR] * gives line of best fit * y int. = R0/ KD * x int.= R0 * slope= -1/KD (R0/ KD/R0) * always negative relationship= negative slope * scatchard equation: y=mx+b [HR]/[H]= -1/KD[HR]+ R0/KD

XIII. ANP. BNP * Atrial Natruretic Peptide (28 amino acids) * Brain Natriuretic Peptide (32 amino acids) * Both circular shape with 2 tails but BNP has longer tails * BNP causes excretion of Na and H2O (antagonist to ADH) XIV. Hypothalamo Hypophyseal Portal System * Primary capillary bed used to pick hormones of hypothalamus released by parvocellular neurons (like TRH) * Secondary capillary bed used to release hormones (TRH) o target cels of anterior pituitary. Also picks up hormones of anterior pituitary and delivers to circulation XV. Hypothalamal hormones that reach ant. Pituitary 1. GHRH Growth Hormones Releasing Hormone * Targets somatotrophes of ant. Pit. That release GH 2. Somatostatin Hypothalamic SS
- targets somatotrophs INHIBITING release of GH 3. TRH
- targets Thyrotropes that release TSH 4. CRH Corticotropin Releasing Hormone * targets corticotrophes of ant. Pit. That releases POMC (Proopio Melano Cortin) * POMC cleaned to make 3 hormones: Beta endorphone, ACTH (Adrenal Cortiotropic hormone) and MSH (Melanocyte Stimulating Hormone) 5. PIH prolactin inhibiting hormone * targets lactotrophes of ant. Pit. * Suppresses production of prolactin (PRL) * TRH may stimulate lactotrophes to release PRL 6. GARH Gonadrotropin releasing hormone * target cell is gonadotrophes of ant. Pit. * Releases FSH and LH (Luteinizing Hormone) XVI. Glycogenolysis, Glucogenesis, and Glyconeogenesis * Normal glucose level in blood: 80-110mg/100mL * Hypoglycemia- less
- alpha cells of pancreas secretes glucagon to increase glucose levels. Glycogen glucose * Hyperglycemia- more * beta cells of islets of Langerhan of pancreas secrete insulin * insulin uses tyrosine kinase to convert glucose to glycogen * Glycogenolysis
- glycogen glucose * Glucogenesis
- carbs (starch) pyruvate glucose * Gluconeogenesis * non-carb precursor glucose * ex: protein/ fat * protein amino acid * fat glycerol/ fatty acids XVII. tropic hormone * hormone that regulates hormonal secretion of an endocrine tissue * ex: TRH released by the hypothalamus regulates TSH secretion of Thyrotropes of ant. Pit. * Ex: TSH released by the thyrotrope of ant. Pit. Regulates T3 and T4 secretion by follicle cells of thyroid * Ex: Growth- hormone- releasing hormone (GHRH) regulates GH secretion of somatotrophes of ant. Pit. * **PRL is NOT a tropic hormone because it induces production of milk by mammary gland (EXOCRINE glad) * Exocrine glands have ducts that release secretions * Endocrine glands are ductless and release secretions into circulation XVIII. Thyroid Gland * Follicle (know how to draw) * 1 layer of cube-like cells surrounding lumen * lumen site for TH synthesis * basolateral membrane and epical membrane * Clear cells (C-Cells) parafollicular (next to follicle) cells that secrete Cacitonin which lowers Ca2+ level in blood by incorporating Ca2+ into bone (calcification). * 4 major proteins suppressed as a result of TSH binding to its receptor at the basolateral membrane of follicular cell: 1. NIS (Na+ iodide symporter) suppressed to allow Na+ and I- to come into cell from circulation. I- moves via trabdcytosis. 2. Sodium- potassium pump 2K+ in and 3Na+ out. ATP ADP 3. Pendrin transports I- into lumen * within the lumen, I- is oxidized to iodide (I0) via enzyme Thyroid Peroxidase (TPO) * TPO also catalyzes the organification step (adding I0 to Tyr units of Tg **be able to draw** * TPO also catalyzes the coupling step (putting MIT and DIT together) to make T3 or T4 (DIT+DIT) **be able to draw** 4. Tg Thyroglobulin containing 123 Tyr units that TPO attached I0 to and is used to synthesize T3/ T4 * transcribed in the nucleus of follicular cell and reaches lumen via exocytosis * Tg loaded with T3/ T4 taken back into cell via endocytosis * Tg+T3/T4 taken into endolysosome (endosome+ lysosome) and T3/ T4 are liberated and exit cell via exocytosis * T3/ T4 then bind to TBG (thyroxine- binding- globulin) in blood for transport in circulation * T3/ T4 are hydrophobic/ lypophilic so need TBG shuttle * T4 (thyroxine or tetraiodothyronine) is form thyroid hormone most commonly produced bc T3 is most active form * T3/ T4 dissociate from TBG when reach target cell and penetrate plasma membrane * Within the target cell, a certain deiodinase removes an iodine from thyroxine converting it to T3 * Mode of action of T3: * once T3 binds to its receptor (which is bound to transcription factor on DNA), it activates DNA transcription (DNA RNA) * activates gene expression leading to cellular metabolism * TH are metabolic hormones * T2 vs. DIT * T2 diiodo thryonine (2 rings) * DIT diiodo tyrosine (1 ring)
**be able to draw all of this** XIX. Deiodinases * Deiodinase class I:
- removes iodine from either inner or outer ring * Deiodinase class II: - removes iodine only from outer ring * Deiodinase class III: * removes iodine only from inner ring * T4 can become inactivated by class I or class III to become reverse T3 (rT3) - mechanism by which you control the amt. of T3 * T3 is in its most active form when I is removed from outer ring (class I or class II) ** be able to draw all of this** XX. Goiters and other Thyroid disorders * Goiter diagnosed at Pendred Syndrome * genetic disorder SLC 26A4: Solute Carrier family 26 member 4 * SLC 26A4 gene encodes pendrin (takes I- from follicular cell to lumen in epical membrane) * Mutated SLC 26A4 will produce dysfunctional pendrin which leads to hypothyroidism * Thyroid gets enlarged bc TSH bombards thyroid bc no T3/ T4 being produced * Cytogenetic location 7q31.1 * Chromosome 7 * Q long arm of chromosome * P short arm * 31 band #31 (#ed starting at centromere and moving away from centromere * 1 subband # * Endemic Goiter * endemic local * not getting enough iodine in diet so body cannot produce T3/ T4 so TSH bombards thyroid and it enlarges * Toxic Goiter Grave’s Disease * autoimmune disorder * antibodies mimic TSH and bind to TSH receptor, over stimulating the follicular cells of thyroid gland * more prevalent in women than men * Post- Pardum thyroiditis
- 3-5 months after giving birth * Hishimotothyroditis * autoimmune disorder * antibodies attack NIS (Na iodide symport) * Congenital Hypothyroidism * mutation in TPO (Thyroid Peroxidase) * TPO: oxidation of iodideIodine, organification iodine--? MIT/ DIT, coupling MIT+ DIT T3 or DIT+DIT T4 * Familial Hyperthyroidism * mutation in transmembrane domain of TSHR (TSH receptor) * transmembrane domain is center domain that is inside the membrane * a gain of function mutation (receptor is stimulated by anything not just TSH) XXI. Calcium Homeostasis: * Regulated by: * PTH raises Ca++ levels in blood * PTH Related Hormones can bind to PTH receptor and activate receptor. Bigger than PTH. * Vit. D * Calcitonin * Normal Calcium level: 9.2-10.4 mg/ 100mL 1) PTH: Calcium ABSORBTION by cells of the small intestine * chief cells in the lobes of the parathyroid secrete PTH * tight conformation of Gq receptor, DAG stimulates PKA which activates many enzymatic rxns including PLA2 (phospholypase A2) * PIP2+ PLA2 liberating arachidoinc acid (know how to draw) * 2 pathways * arachidoinc acid +lypooxygenase Leukotrienes (Leukotrienes degrade the pre-formed PTH as a result of hypercalcemia- Ca2+ receptor in tight confirmation) * arachidonic acid + cyclooxygenase prostaglandins/ prostacyaines * both leukotrienes and prostaglandins are Eicisanoids (20 C; inflammatory rxns, paracrine sugnals)
**know how to draw ** 2) PTH also stimulates Ca++ REABSORBTION by cells of kidney tubules * in the small intestine or kidney tubule: * PTH binds to PTH Receptor 1 and Vit. D diffuses into cell * PTH activates DNA to transcribe to make Ca2+ channels so that Ca2+ can leave the lumen * Vit. D activates DNA to transcribe calbindin, which binds Ca2+ ion to keep intracellular level of Ca2+ low so Ca2+ will keep coming through channel * Calcium ATPase needs ATP to transport Ca2+ from high to low conc. (active transport)- Vit. D dependent
**know how to draw** 3) PTH stimulates Ca2+ RESORPTION from bone * osteroblasts- immature bone cells that become osteocytes. Produces RANKL [Receptor Activator of Nuclear factor KApa beta Ligand] * RANKL: produced by osteroblasts in response to Vit. D, PTH, PTHrP. * All stimulate osteoclasts, so are called proresorptive (because they cause resorption) and calcitropic factors (increase Ca2+ levels in blood). * osteoclast precursor cell [not yet osteoclast]- activated into osteoclast after binding of RANKL to RANK (receptor for RANKL) * osteoclast- multinucleated cell that degrades bone * as a result , ca2++ is released from bone and Ca2+ resorption takes place * Ca2+ is used to synthesize new bone tissue * Osteoprotegerin (OPG) can bind to RANKL preventing osteoclast precurser cell from maturing to osteoclast; osteoclastogenesis inhibitory factor * OPG produced by osteoblasts in response to estrogen, calcitonin, BMP (Bone Morphogenic Protein), and THPO (Thrombopoietin) * All kill osteoclasts (anti- resorptive factors against bone absorption) * Cytokine TPO (which regulates platelet levels) has been shown to induce OPG expression, leading to abnormal increase in bone density * Thrombopoietin (THPO) stimulates production of thrombocytes (platelets) * Thrombo-opoiesis production of platelets * Erythropoietin stimulates production of erythrocytes (EPO)- erythropoiesis * Both THPO and EPO are released by kidneys * Remember difference in TPO and THPO * Estrogen activates OPG production helps women prevent bone loss until menopause * Selective Estrogen Receptor Modulators (SERMs) given to women, bind to estrogen receptor in bone tissue and activate but deactivate in other tissues. Agonist for estrogen receptor in bone tissue but act as antagonist of the same receptor in other tissues (like breast) and can prevent breast cancer. * Menopause estrogen goes down, OPG goes down, RANKL bind to RANK and stimulates osteoclast and bone degration occurs * Vit. D stimulates bone synthesis and PTH inhibits bone synthesis by keeping Ca2+ in blood. * Vitamin D does the same thing as PTH
**know how to draw** * Vitamin D synthesis: 1) Cholesterol

2) 7 dehydrocholesterol in keratinocytes of skin
Sunlight and heat
Sunlight and heat

3) cholicalciferol [aka vitamin D3]
Leaves keratinocytes to go to liver
2-5 hydroxylase in liver
Leaves keratinocytes to go to liver
2-5 hydroxylase in liver

4) 2,5-hydroxycholicalciferol [aka calcidiol] in liver cells [hepatocytes]
Leaves liver to go to kidney
1-hydroxylase in kidney [activated by PTH]
Leaves liver to go to kidney
1-hydroxylase in kidney [activated by PTH]

5) 1,2,5-dihydroxicholicalciferol [aka calcitriol and vit. D] * active form of vit. D
**know how to draw synthesis of vit D** * too much vit. D synthesis stops PTH production by destabilizing the PTH mRNA so mRNA will not be translated by ribosome into PTH * hypercalcemia can also stop production of PTH XXII. water conservation * V1R (Vasopresion type 1 receptor) * Receptor for AVP (Argenine Vasopression) aka ADH (Anti-diuretic hormome) * Know how to draw * Like oT, AVP is released from magnocellular neurons of hypothalamus and stores in posterior pituitary * oT and AVP use hypothalamo hypophyseal tract to deliver oT and AVP to post. Pit. * Location: smooth muscle cells of kidney arterioles * Uses Gq GCPR to make smooth muscle cell contract bc Ca2+ binds to camodulin * V2R (Vasopression Type 2 Receptor) * Ligand: AVP/ ADH * Uses Gs GPCR * Location: cells of collecting duct plasma membrane * Causes conservation of H2O * Nephron filtration unit in kidney * blood enters afferent arteriol and through capillaries of Glomerulus * filtrate is collected in Bowman’s capsule while blood exits via efferent arteriol * filtrate goes through the proximal convoluted tubule, down descending limb, loop of henle, up ascending limb of loop of henle, and into collectory duct * AVP binds to V2R (Gs receptor) which stimulates gene expression of aquaporin 1, 2, and 3 because cAMP acts as 2nd messanger and stimulates PKA which will stimulate transcription factors * 5L of blood in body; 180L of blood filtered/ day (glomerular filtration rate)
**know how to draw** * This is not the only method for water conservation XXIII. Diabetes Insipides * Neurogenic central source * AVP production problem * Cytogenic location 20p13 (gene that produces AVP) * Desmopression D-Argenine Vasopression (DDAVP) synthetic analogue of vasopression. This includes D Argenine (more stable than L found in body). Used to treat neurogenic diabetes insipides. * Nephrogenic peripheral source * Could be V2R problem * Cytogenic location Xq28 which codes V2R receptor * Could be AQP2 problem * Cytogenic location 12q13 which codes protein H2O channel ** situs inversa organs switched right to left because of patterning proteins (like BMP in serine- kinase) XXIV. Adrenal Gland: * Above kidney * 3 layers of adrenal cortex (outer to inner layer): 1. zona glomerulosa secretes mineral corticode Aldosterone which targets kidney tubules and conserves Na+ and H2O. cannot secrete any other steroid hormone because lacks 17-hydroxylase activity; only one with aldosterone synthase activity 2. zona fasciculate secretes cortisol (glucocorticoide) and DHEA (dehydro Ep Androesterone) sex hormone 3. zona reticularis secretes cortisol (glucocorticode) and DHEA * Adrenal medulla secretes epinephrine and norepinephrine
**be able to draw XXV. Sterioidogenesis
** steps 1-3 can occur in all cells with cholesterol 1. Delivery of cholesterol droplets of Low- Density- Lopoproteins (LDL) into cell by Receptor-mediated endocytosis (Draw).

2. Delivery of cholesterol from outer membrane of mitochondria to inner membrane of mitochondria by StAR (Steriodogenic Acute Regulator) Protein (Draw)

3. Action of P450SCC (20-22 desmolase): cholesterol (27C) pregenolone (21C)

4. Aldosterone synthesis (happening in zona glomerulosa of adrenal cortex). Draw:

* Complications: * mutations in the genes responsible for the receptor-mediated endocytosis results in Familial Hypercholestrolemia (FH) * mutations with StAR will keep cholesterol in cytoplasm and not into the mitochondria * Mode of action of aldosterone as a mineral corticoid (conserves Na+ and H2O by working in cells of kidney tubules) * aldosterone penetrates the plasma membrane and binds receptor in cytosol * dimerization may take place (of HR complex) * diamer penetrates nuclear envelope and binds to DNA promotor site to activate transcription of certain genes; specifically Na+ channel protein to be inserted into epical membrane and NA+ K+ ATPase into basolateral membrane * 1st Na+ transporte from lumen of kidney tubule to cells od kidney tubules by Na+ channel. * Then out to interstacial fluid by NA+ K+ ATPase. H2O follows by osmosis Na+ and H2O conserved * Aldosterone increases blood volume so increases BP; needed for hypotension. * Renin- Angiotensin- Aldosterone Mechanism * in case of hypotension (low BP), kidney cells secrete Renin * angiotensin large protein (453 amino acids) * renin secreted by kidneys; removes amino acids from angiotensin to form Angiotensin I (AgI) * Angiotensin converting enzyme (ACE converting enzyme) produced by endothilia of respiratory system; acts on AgI to form octapeptide called ANgiotension II (AgII) * Roles of AgII: 1. Vasoconstriction of blood vessels (powerful vasoconstriction) increase in BP/ blood volume 2. Targets cells of zona glomerulosa that releases Aldosterone through renin- angiotension- aldosterone mechanism 3. Also targets magnocellular neurons of hypothalamus to secrete AVP to conserve H2O; BP and blood volume increases. 4. Also targets cells of adrenal medulla to secrete epinephrine and norepinephrine * Cortisol Sythesis: (draw)

* cortisol is a glucocorticoid dealing with glucose metabolism * because of similarity between cortisol and aldersterone, the mineral corticoid receptor binds to and activated by cortisol not good because you retain too much H2O * kidneys must deactivate cortisol by enzyme 11-BHSD2 (11- Beta Hydroxy Steroid Dehydrogenase Type 2) in cortisol- cortisone stunt (draw) * physiological effects of cortisol * cortisol has a glucose- sparing effect; too much cortisol is too much muscle wasting 1. degradation of proteins into amino acids used in glucose formation (gluconeogenesis) 2. activation of enzymes of gluconeogenesis * pyruvate carboxylase * phosphoenol pyruvate carboxy kinase * fructose 1,6 biphosphatase * glucose 6 phosphatase 3. inhibits protein synthesis * ex: inhibition of PLA2 production and inhibition of cyclooxygenases which prevents formation of eicosanoids (inflammatory ) * cortisol – anti-inflammatory * pregnisone- synthetic cortisol- anti-inflammatory drug 4. degradation of body fat and mobilization of free fatty acids to produce glucose (gluconeogenesis) * androstenediol and testosterone and testosterone
- DHEA and all other adrenal androgens are 19C molecules bc of the action of 17-20 lyase (unlike cortisol and aldosterone which are 21C because of P450SCC cutting C 20-22) * XXVI.

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