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M2 Flashcards

1
Q

PNMT

A

phentolamine N-methyltransferase

  • converts NE ➔ EPI
  • only expressed in chromaffin cells in adrenal medula
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2
Q

inflammatory response

A
  • inflammation = results of 1st line of defense (innate)
  • initiated on site of antigen contact
  • clinical signs:
    • tumor (swelling): ➔ edema from blood
    • rubor: redness
    • calor: heat ➔ tons of metabolic activity generates heat
    • dolor: pain
    • tumor ➔ enlarged site b/c extra cells migrate to area
    • functio laesa: loss of fx ➔ tissue busy fighting injury
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3
Q

immune system

A

2 levels of immune defense:

  • innate - 1st line
    • antigen presenting cells ➔ macrophages, dendritic cells, neutrophils
    • phagocytosis of antigens at site of injury
    • antigen processing & presentation
    • production of pro-inflammatory cytokines: interleukins (IL) & tumor necrosis factors (TNF)
  • acquired - 2nd line
    • attract other immune cells
    • build immune memory
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4
Q

eicosanoids

A

signaling molecules made by oxidation of fatty acids

  • cytokines: pro-inflammatory mol that attract other cells to mount stronger immune response
    • IL: interleukins
    • TNF: tumor necrosis factors
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5
Q

inflammation pathway

A

phospholipase A2 releases arachidonic acid from PM & converts them into eicosanoids

  • CYTP450 epoxygenase converts arachidonic acid into epoxyeicosatrienoic acids (EETs)
  • cox 1 & cox 2 convert arachidonic acid into prostanoids:
    • prostaglandins
    • prostacylin (PGI2)
    • thromboxane (TXA2)
  • lox converts arachidonic acid into HETEs:
    • leukotrienes
    • lipoxins
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6
Q

cortisol action on inflammatory pathway

A

cortisol blocks phospholipase A2 ➔ inhibits entire inflammation pathway

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7
Q

arachidonic acid

A

precursor of pro-inflammatory eicosanoids

  • released from PM by phospholipase A2
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8
Q

NSAID action on inflammatory pathway

A

block cox 2 ezyme ➞ inhibit prostanoids

  • EETs & HETEs still synthesized
  • minimize inflammatory response
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9
Q

glucocorticoid: innate immunity regulation

A

↓ pro-inflammatory mol

  • ↓ prostaglandin synthesis
  • ↓ cytokine production

↓ cell-mediated immune response

  • ↓ vascular permeability
  • ↓ mast cell #s
  • ↓ antigen-presenting cell #s
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10
Q

glucocorticoid: acquired immunity regulation

A

↓ differentiation of antigen-fighting cells

  • inhibits T & B lymphocytes in circulation
  • inhibits synthesis of immunoglobulins

stimulates lymphocyte apoptosis ➔ removes antigen-fighting cells from circulation

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11
Q

embryonic origin of adrenal cortex

A

mesoderm

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12
Q

embryonic origin of adrenal medulla

A

neural ectoderm

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13
Q

adrenal medulla hormones

A

EPI, NE, dopamine

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14
Q

cells of the adrena medulla

A

chromaffin cells (pheochromocyte): synthesis & storage of catecholamines (NE, EPI)

  • highly specialized neural system originating in neural crest that make up the adrenal medulla
  • migrate to adrenal medulla & paraganglia during embryo/fetal development
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15
Q

epinephrine synthesis

A

tyrosine ➔ dopamine (dopamine β-hydroxylase - DBH) ➔ NE (PNMT) ➔ EPI

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16
Q

enzyme that converts NE to EPI

A

PNMT: phentolamine N-methyltransferase

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17
Q

epinephrine

A
  • synthesized from NE
  • precursor mol: tyrosine
  • produced exclusively by adrenal medulla cells (main product ~80%)
    • NE present in CNS, adrenal medulla, & sympathetic neurons
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18
Q

adrenal medulla neurons innervated by:

A

SNS

  • sympathetic cholinergic preganglionic neurons originate from thoracic & lumbar regions
  • nerves synapse at ganglia outside of spinal cord
  • stimulates adrenal medulla to secrete catecholamines
  • directly stimulates CO: directs bf to muscles & diverts bf away from visceral organs
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19
Q

adrenal medulla glucocorticoid affinity

A

adrenal medulla has GCR ➞ able to immediately respond to newly synthesized cortisol

  • cortisol acts locally on neighboring medulla cells
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20
Q

SNS input: normal vs adrenal medullary

A

normal:

  • short cholinergic preganglionic neurons release ACh to paraganglion with nicotinic cholinergic receptors
  • long adrenergic postganglionic neurons release NE to target organ/tissue with adrenergic receptors

adrenal:

  • long cholinergic preganglionic neurons release ACh into nicotinic cholinergic receptors in adrenal medulla
  • adrenal medulla secretes EPI

neurons release NE, medulla secretes EPI

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21
Q

effects of EPI

A

fight or flight response: extremely fast response mediated by nervous reflex, EPI release from adrenal medulla, & NE release in adrenergic synapses

  • lipolysis
  • ↑ breakdown of hepatic glycogen
  • ↑HR (tachycardia) ➞ chronotropic effect: effects ↑ (speed up) time
  • ↑SV ➞ strength of contraction ➞ inotropic effect: effects ↑ efficiency (strength of contraction)
  • peripheral vasoconstriction ➞ blood redirected where it’s needed
  • ↑BP
  • dilation of coronary arteries (↑ perfusion to heart)
  • dilation of muscle vessels (↑ perfusion to muscles)
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22
Q

catecholamines

A

DA: dopamine
EPI: epinephrine
NE: norepinephrine

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23
Q

catecholamine biosynthesis

A
  • tyrosine = precursor
    • from food or liver synthesis from phenylalanine
  • DBH = dopamine β-hydroxylase: converts dopamine ➔ NE
  • PNMT = phentolamine N-methyltransferase: converts NE ➔ EPI
    • 10:1 EPI:NE
    • cortisol stimulates PNMT synthesis ➞ can convert more (still possible w/out cortisol)
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24
Q

epinephrine response to hypoglycemia

A
  1. stimulates HSL enzyme to ↑ lipolysis
  2. stimulates glycogen phosphorylase to break down glycogen
  3. inhibits glycogen synthesis
  • 2 & 3 oppose cortisol: EPI is breaking glycogen that cortisol is making
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25
Q

EPI & NE effects

A
  • NE fxs primarily as a neurotransmitter for cardiac effects
  • both NE & EPI influence vascular tone
  • EPI affects metabolic processes (e.g carbohydrate metabolism)
  • ↑ RR
  • ↑ bf to skeletal muscles
  • intestinal muscles relax
  • pupils dilate
  • ↑BP
  • ↑BG
  • ↑HR
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26
Q

catecholamines & adrenergic receptors

A
  • 5 types of adrenergic receptors: ⍺1, ⍺2, β1, β2, β3
  • located in diff parts of body
  • extent of action depends on how much of the hormone is present
  • at higher levels: catecholamines can also bind to receptors with lower affinity
  • GPCRs
  • at ↓[plasma]: EPI predominantly stimulates β-adrenergic receptors causing vasodilation
  • at ↑[plasma]: EPI stimulates ⍺-adrenergic receptors sufficiently to override vasodilation & cause vasoconstriction
  • each adrenergic receptor subtype is encoded by a diff gene
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27
Q

main receptor type for EPI at low concentrations

A

β2-adrenergic receptor

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28
Q

main receptor for EPI during high concentrations (during fight-or-flight)

A

⍺2-adrenergic

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29
Q

⍺1-adrenergic receptor pathway

A

Gq alpha subunit using phospholipase C to convert PIP2 to IP3 & DAG

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30
Q

⍺2 adrenergic receptor pathway

A

Gi ⍺ subunit inhibiting adenylyl cyclase

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31
Q

β adrenergic receptor pathway

A

Gs ⍺ subunit using adenylyl cyclase to convert ATP to cAMP

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32
Q

Gi alpha subunit GPCR

A

inhibitory: blocks adenylyl cyclase

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33
Q

⍺1-adrenergic affinity

A

NE > EPI

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34
Q

⍺1-adrenergic agonist

A

phenylephrine

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35
Q

⍺2-adrenergic G protein, linked enzyme, &
second messenger

A

Gi ⍺ subunit inhibits adenylyl cyclase to ↓ cAMP

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36
Q

β1-adrenergic tissue & action

A
  1. ↑ force & rate of contraction in myocardium
  2. ↑ renin secretion in JGC cells of kidney
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37
Q

β2-adrenergic G protein, linked enzyme, & second messenger

A

Gs protein using adenylyl cyclase to ↑ cAMP

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38
Q

β3-adrenergic G protein, linked enzyme, & second messenger

A

Gs protein using adenylyl cyclase to ↑ cAMP

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39
Q

β3-adrenergic agonist

A

BRL37344

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40
Q

β3-adrenergic affinity

A

NE > EPI

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41
Q

β2-adrenergic agonist

A

isoproterenol

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42
Q

β2-adrenergic affinity

A

EPI > > > NE

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43
Q

β1-adrenergic G protein, linked enzyme, & second messenger

A

Gs alpha subunit using adenylyl cyclase to ↑ cAMP

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44
Q

β1-adrenergic agonist

A

dobutamine or isoproterenol

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45
Q

β1-adrenergic affinity

A

EPI =NE

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46
Q

⍺2-adrenergic agonist

A

xylazine

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47
Q

⍺2-adrenergic affinity

A

NE > EPI

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48
Q

⍺1-adrenergic tissue & action

A
  1. vasoconstriction (↑ BP)
  2. contracts spleen expelling blood
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49
Q

⍺1-adrenergic G protein, linked enzyme, & second messenger

A

Gq using phospholipase C to↑ IP3, DAG, & Ca

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50
Q

⍺2-adrenergic tissue & action

A

↓ neurotransmitter release in preganglionic neurons

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51
Q

β2-adrenergic tissue & action

A
  1. vasodilation (↑ bf)
  2. bronchial dilation
  3. ↑ glycogenolysis & gluconeogenesis in liver
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52
Q

dopamine receptors

A
  • not adrenergic receptors
  • GPCRs
  • subcategories: D1-like & D2-like
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53
Q

dopamine-2 receptor tissue & action

A

inhibits prolactin release in pituitary lactotrophs

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54
Q

dopamine fx

A

important in the brain/CNS & as a paracrine signaling mol

55
Q

effects of circulating EPI

A
  • ↑ HR & inotropy (β1)
  • vasoconstriction in most systemic arteries & veins (⍺1)
  • vasodilation in muscle & liver vasculatures at low concentrations (β2) & vasoconstriction at high concentrations (⍺1)
  • @ low-to-moderate circulating [EPI]: ↑ CO & redistribution of CO to muscular & hepatic circulations w/ only a small change in MAP b/c systemic vascular resistance falls due to β2-adrenoceptor activation
  • @ ↑ plasma [EPI]: MAP ↑ b/c of binding to ⍺-adrenoreceptors on bv that offsets β2-adrenoceptor vasodilation
56
Q

pheochromocytomas

A
  • catecholamine-secreting tumors from chromaffin cells of adrenal medulla
  • relatively rare: ≤0.5% of hypertensive patients
  • secrete mainly NE
  • episodes of ↑ catecholamine secretion cause hypertension, palpitation, headache, & sweating
57
Q

aldosterone

A
  • mineralocorticoid
  • synthesized in zona glomerulosa
  • steroidogenesis pathway: cholesterol (cholesterol desmolase) ➔ pregnenolone (3β-HSD) ➔ progesterone (21⍺-hydroxylase) ➔ 11-deoxycorticosterone (P450c11/11β-hydroxylase) ➔ corticosterone (p450aldo/adosterone synthase) ➔ aldosterone
  • NO p450c17 (17⍺hydroxylase or 17,20-lyase)
  • NO 17β-HSD
58
Q

ECF

A
  • intravascular space (lymphatic, blood)
  • interstitial space occupied by fluids
59
Q

functional unit of the kidney

60
Q

majority of Na reabsorption in the kidneys

A

proximal tutbule & loop of Henle via countercurrent system (~94%)

  • not under endocrine control
  • remaining Na will be reabsorbed in the principle cells of the collecting duct in response to aldosterone
61
Q

actions of aldosterone

A
  • kidney = major site
  • binds to MR in target cell & affects transcriptional changes typical of steroid hormone receptor
  • retains Na & water in body (water follows Na)
  • stimulates Na reabsorption in principal cell of collecting duct
    • facilitates transcription of Na/K ATPase pumps in basolateral membrane → pumps Na back into blood & K into cell
    • stimulates Sgk1 to inactivate Nedd4-2 channels → inactivated Nedd4-2 channels cannot destroy ENaC (Na channels) ∴ Na can re-enter cell via apical membrane
  • ↑ BP by ↑ ECF volume (intravascular fluid predominantly)
  • ↑ urine excretion of K & H+
    • stimulates expression of K channels in apical membrane
62
Q

aldosterone & Na

A

man fx = conserving body Na to sustain ECF volume

  • when body Na is depleted, fall in ECF & plasma volume ↓ renal arterial bf & pressure
  • aldosterone is largely secreted in response to signals that arise from the kidney when a reduction in circulating fluid volume is sensed
63
Q

aldosterone & K

A
  • aldosterone facilitates K removal from ECF
  • ↑ K stimulates aldosterone synthesis
    • K depletion (hypokalemia) = ↓ aldosterone secretion
    • hyperkalemia = ↑aldosterone
  • aldosterone is critical for disposal of daily dietary K load to maintain normal plasma [K]
  • stimulation of aldosterone synthesis by K: depolarization of zona glomerulosa cell membrane opens Ca v-gated channels ➞ ↑ in intracellular Ca stimulates expression of CYP11B2 (P450aldo/aldosterone synthase
64
Q

regulation of aldosterone

A
  • stimulated by:
    • K
    • angiotensin II
    • ACTH (minimal)
  • inhibited by: atrial natriuretic peptide (ANP) ➔ involved in diuresis
  • renin: enzyme produced in juxtaglomerular cells on afferent arteriole that converts angiotensinogen ➔ angiotensin I
    • pathway to ↑BP, ↑[Na], ↑ECF V
    • control of renin release:
      1. baroreceptors in JGC detect renal perfusion pressure
      2. macula densa cell chemoreceptors detect levels of Na & Cl in filtrate & communicate with adjacent JGC cells to release renin at low [NaCl]
    • factors that stimulate renin release:
      1. ↓BP
      2. ↓[Na]
  • afferent arteriole brings unfiltered blood to kidney
  • efferent arteriole brings filtered blood out of kidney
65
Q

renin-angiotensen-aldosterone system (RAAS)

A
  1. macula densa cells in distal tubule detect ↓ [NaCl] & JGC detect ↓BP in afferent arteriole ➔ JGC release renin
  2. renin converts angiotensinogen ➔ angiotensin I (precursor)
  3. ACE (angiotensin converting enzyme) produced mainly in lungs converts angiotensin I ➔ angiotensin II (potent vasopressor)
  4. angiotensin II stimulates:
    1. SNS ➔ release catecholamines from adrenal medulla to stimulate vasoconstriction
    2. transcription of P450aldo ➔ ↑ aldosterone: reabsorption of Na & Cl in kidney to retain water
    3. vasoconstriction ➔ ↑ BP & ↑ renal bf
    4. AVP secretion in neurohypophysis ➔ ↑ water reabsorption
  5. normal perfusion removes stimulus & acts as ⊖ feedback
66
Q

angiotensin II actions

A

maintain normal ECF V & BP

  • ↑ transcription of P450aldo ➞ ↑ aldosterone production
  • vasoconstriction ➞ ↑BP ➞ ↑renal bf
  • release of EPI & NE from adrenal medulla ➞ enhance actitivty of SNS & NE release in nerve terminals
  • promote release of AVP ➞ water reabsorption in kidneys
67
Q

angiotensin II receptors

A

AT1 & AT2

  • AT1:
    • adrenal, CV, & renal
    • Gq GPCR
  • AT2 associated w/ other effects (e.g. growth, differentiation) that may be opposed to AT1
68
Q

ANP

A
  • atrial natriuretic peptide
  • inhibits aldosterone
  • secreted by atrial myocytes in response to volume expansion
  • binds to receptors in zona glomerulosa to directly inhibit aldosterone synthesis
  • ↓ aldosterone indirectly by inhibiting renin-release
  • acts via intracellular cGMP which opposes cAMP
  • effects: vasodilation, hyperfiltration, & natriuresis (Na excretion)
    • ↑ GFR
    • inhibits Na & water reabsorption in principal cells of collecting duct
    • inhibits secretion of renin, aldosterone, AVP, & ACTH
69
Q

hyperaldosteronism (primary aldosteronism)

A
  • primary overproduction of aldosterone with low renin
  • Conn’s syndrome
  • characterized by ↑BP from ↑ retention of NaCl & H2O by kidneys + ↓ serum [K] (hypokalemia) from excess K secretion in urine
  • causes:
    • benign adrenal tumor (adenoma)
    • hyperplasia of 1 or both adrenal glands (idiopathic: unknown cause)
70
Q

aldosterone in target cells

A
  • main targets of aldosterone: principal cell in the collecting ducts, colon epithelial cells, & sweat glands
  • ↑ K channels in apical membrane to excrete more K
  • ↑ Na/K ATPase pumps in basolateral membrane to pump Na out of cell into blood & K into cell (out of blood) where it can move through channels in apical membrane to be excreted in urine
  • ↑ expression of Sgk1 to inactivate destruction complex for Na channels to keep them in membrane
    • ENaC = epithelial Na channel ➔ brings Na back from lumen into cell
    • ubiquitin = system cells use to recycle mol ➔ tags cells & targets for destruction
    • Nedd4-2 = ubiquitin protein that targets & destroys Na channels
    • Sgk1 (serum-and-glucocorticoid kinase) phosphorylates Nedd4-2 ➔ inactivates them
    • aldosterone stimulates Sgk1 ➔ Nedd4-2 cannot destroy ENaC
71
Q

11β-hydroxysteroid dehydrogenase (11β-HSD)

A

enzyme that converts cortisol ➔ cortisone (inactive form)

  • cortisol has good affinity for mineralocorticoid receptor & because plasma [cortisol] > than [aldosterone] cortisol would occupy all MCR
  • aldosterone ≠ substrate for 11β-HSD
72
Q

Tg synthesis

A

synthesized in ER of thyrocyte & packaged into exocytosis vesicles that fuse w/ apical membrane releasing contents into colloid

  • contains tyrosyl residues that can be iodinated
  • stimulated by TSH
73
Q

thyroid gland anatomy

A
  • surrounded by collagenous connective tissue where parathyroid glands are located
  • thyrocyte = TH producing cell (follicular cell)
    • functional unit of thyroid gland
    • produce & release TH in response to TSH
  • colloid = viscous gel composed of iodinated thyroglobulin
    • extracellular stoage of TH & thyroglobulin
    • storrage of iodine
    • where TH is synthesized
74
Q

general fx of thyroid gland

A
  • production of TH
  • production of calcitonin
75
Q

HPT axis

A
  • TRH released from PVN
  • stimuli:
    • cold temp
    • adrenergic input
    • metabolism & energy balance from Arc nucleus
  • T3 is the main effector of negative feedback
76
Q

Tg

A

thyroglobulin = TH precursor

  • glycoprotein synthesized in thyrocyte & packaged in exocytosis vesicles
  • contains tyrosil residues that can be iodinated
77
Q

T4

A

thyroxine (tetraiodothyronine) = prohormone

  • longer 1/2 life ➞ more stable
  • storage form
  • less affinity binding to THR than T3
  • 5’ iodine
  • only synthesized in thyroid gland
78
Q

T3

A

triiodothyronine = most potent active form

  • no 5’ iodine
79
Q

rT3

A

reverse T3 = inactive form

  • control mechanism for TH level regulation
  • no 5 iodine
80
Q

thyrocyte

A

follicular cell ➔ TH-producing cell

  • produce & release TH in response to TSH
81
Q

thyrotroph cell receptor

A
  • Gq ⍺ subunit GPCR
  • Ca & PKC involved in activation of transcription of TSH gene
  • TRH also promotes glycosylation of TSH gene making TSH biologically active
82
Q

TSH stimulates:

A
  1. iodine uptake via NIS
  2. Tg synthesis
  3. Tg iodination
  4. deposition of Tg in colloid
  5. colloid uptake into follicular cells (thyrocytes)
  6. proteolysis of Tg (T3/T4 production)
  7. immediate release of T3/T4 from colloid storage
  8. follicular cell metabolism & cell growth
83
Q

short-term effecft of TSH

A

activated PKA stimulates:

  1. hypertrophy of thyroid cells
  2. activation of iodine pumps (NIS)
  3. Tg exocytosis
  4. TPO activity
  5. induces pseudopods to ↑ Tg reabsorption at colloid border
  6. lysosome-mediated proteolysis of Tg
84
Q

long-term effects of TSH

A

expression of (synthesis via transcription):

  • Tg
  • thyroid peroxidase (TPO)
85
Q

NIS

A

Na/I symporter = pump that actively transports I (& Na) into thyrocyte across the thyrocyte basolateral membrane

  • activated by binding TSH to its receptor
  • disorders of NIS associated w/ hypothyroidism
    • inactivating mutation of the NIS gene: congenital hypothyroidism
    • autoimmune disease = antibiodies against NIS: acquired hypothyroidism
86
Q

congenital hypothyroidism cause

A

inactivating mutation of the NIS gene

87
Q

acquired hypothyroidism

A

autoimmune disease where the body produces antibodies against NIS

88
Q

TPO fx

A

thyroid peroxidase:

  • oxidation of iodine
  • iodination (organification) of thyroglobulin
  • coupling of MIT & DIT to form T3 & T4
89
Q

circulating TH

A
  • T4 = primary secretory product of thyroid gland
    • thyroid = only source of T4
  • T3 = most potent/active form
    • derived from 2 processes:
      1. ~80% deiodination of T4 in peripheral tissues (primarily liver but also kidneys & others)
      2. ~20% direct thyroid secretion
90
Q

where is T3 produced

A
  1. ~80% deiodination of T4 in peripheral tissues (primarily liver but also kidneys & others)
  2. ~20% direct thyroid secretion
91
Q

synthesis of TH

A

T3 & T4 made of iodinated Tg

  1. iodine is oxidized by TPO activity
  2. tyrosine residues on Tg are iodinated (iodination/organification)
  3. iodination of tyrosines yields MIT & DIT: adding iodines
  4. coupling = binding of MIT & DITs (catalyzed by TPO) to get T3 & T4
  5. pendrin channels in apical membrane transport I into colloid (not TSH-dependent − always there on a [gradient])
92
Q

transport & delivery of TH

A
  • transported via plasma carriers: thyroid-binding globulin (TBG), albumin, transthyretin (<0.5% is unbound)
  • plasma carrier fx:
    1. occupy space on TH ∴ only free portion of TH not bound to carrier is available to enter target cell & become metabolically active
    2. extend TH half-life by protecting from degradation
    3. maintain large circulating pool of TH
93
Q

autoregulation of thyroid gland

A
  • thyroid gland can modify its activity independent of TSH to adapt to changes in iodine availability
  • in response to iodine deficiency:
    • ↑ iodine transport efficiency
    • T3 preferentially synthesized over T4
  • in response to iodine excess:
    • many thyroid fx suppressed (primarily by inhibiting NIS i.e. Wolff-Chaikoff effect aka iodide block)
94
Q

TH receptors

A
  • nuclear receptors ∴ intracellular
    • thyroid receptor superfamily ➞ form heterodimers w/ retinoic acid (retinoid x − RXR) inside nucleus
    • TRE = thyroid response element
  • 2 types: TR⍺ & TRβ w/ isoforms
    • TR⍺1
    • TR⍺2
    • TRβ1
    • TRβ2
95
Q

mechanism of action of TH receptors

A
  1. monocarboxylate transporter (MCT8) = highly specific transporter ➞ carries TH across PM
  2. binding of T3 dislocates co-repressors & activates co-activators (or vica-versa)
    • co-regulator proteins = co-activators (CoA) & co-repressors (CoR)
    • CoR bind to TR inactivating it
    • T3-binding exchanges CoR with CoA
    • sometimes TR has a CoA bound already & is actively transcribing ➞ T3 binding changes CoA ➔ CoR so binding represses gene transcription
  3. modulation of gene expression in target cells
96
Q

gene expression regulation by TH receptors (TR)

A
  • binding of TRs to DNA is independent of hormone binding
  • TRs bind to DNA as:
    • homodimers: combination of TR isoforms (⍺, β)
    • heterodimers: associated w/ other nuclear receptors − most commonly retinoid X receptor (RXR)
97
Q

TR regulation: variables involved in specificity of cell response

A
  • # of TRs
  • relative expression of subtype of TR (TR⍺ &/or TRβ)
  • expression & activity of co-regulators
98
Q

TH control at multiple levels

A
  1. hormone synthesis can autoregulate depending on iodine availability
  2. T4 converted to T3 on demand
  3. multiple carrier proteins ensure that TH is stable in circulation: thyroid-binding globulin (TBG), transthyretin, albumin
  4. deiodinases are present in a variety of tissues
99
Q

epinephrine & cortisol similarities

A

synergistic response with cortisol:

  • maintaining/↑ levels of glucose
  • stopping immune system in response to stressor
100
Q

colloid

A

viscous gel composed of iodinated thyroglobulin

  • extracellular storage of TH & thyroglobulin
  • storage of iodine
  • where TH is synthesized
101
Q

levels of endocrine disorder

A
  1. primary ➔ problem is in the endocrine gland
  2. central ➔ problem is in hypothalamus
  3. secondary ➔ problem is in the pituitary gland
102
Q

cushing’s syndrome

A

hyperadrenocorticism

  • excess circulating cortisol or glucocorticoids
  • ACTH-independent: ↑ cortisol but not from adrenal gland being overstimulated
    • most commonly iatrogenic: induced by tx given to animals by humans
  • ACTH-dependent: pituitary or non-pituitary tumors secreting ACTH or CRH ➔ Cushing’s disease
    -
103
Q

cushing’s disease

A

excess circulating cortisol or glucocorticoids from tumors

ACTH-dependent hyperadrenocorticism

  • pituitary-dependent: pituitary tumor producing ACTH ➔ hyperstimulation of adrenal gland
  • ectopic ACTH expression by nonpituitary tumor cells: POMC precursor incorrectly cleaved to release ACTH
  • bilateral hyperplasia of zona fasciculata & zona reticularis

ACTH-independent hyperadrenocorticism from adrenal tumor secreting excess cortisol/glucocorticoids

104
Q

cushing’s syndrome/disease symptoms

A
  • atrophy of epidermis & connective tissue ➞ skin thinning & alopecia
  • centripetal obesity: visceral fat accumulation ➞ pendulous abdomen
  • dehydration
  • osteoporosis
  • muscle weakness
  • polyphagia: feeling of extreme insatiable hunger
  • exophthalmos: bulging eyes
  • bruising & poor healing
  • pruritus: itching
  • acne
  • hyperpigmentation
105
Q

addison’s disease

A

hypoadrenocorticism:

  • associated w/ mineralocorticoid deficiency
  • primary hypoadrenocorticism = glucocorticoid deficiency at adrenal level
    • congenital adrenal hyperplasia = deficiency of enzyme P450c21 → not producing enough GC
  • causes:
    • autoimmune
    • infectious
    • congenital
    • iatrogenic
  • symptom: hyperpigmentation
106
Q

addison’s disease symptoms

A
  • hyperpigmentation
  • hypoglycemia
  • changes in body hair distribution
  • GI disturbances
  • weakness
  • weight loss
  • postural hypotension
107
Q

deiodinases

A

family of enzymes that de-iodinate iodotyrosines in TH mol

  • no way to add I after synthesis
  • peripheral metabolism of TH
  • serves 2 purposes:
    1. ensures availability of circylating & tissue-specific T3
    2. ensures levels of TH remain w/in physiological range via deactivation of T4 & T3
  • 5’-deiodinase (D1 & D2) removes the I at the 5’ position to activate T3
  • 5-deiodinase (D3) removes the I at the 5 position to convert it to rT3 & inactivate it
108
Q

5’-deiodinase

A

removes the I at the 5’ position to activate T3

  • D1:
    • kidney, liver, skeletal muscle (& small amount in the thyroid gland)
    • 5’ monodeiodination forms T3 ➞ active form
    • most abundant
    • in PM of cells ➞ ensures adequate circulating levels of T3
  • D2:
    • brain & pituitary gland
    • in ER close to nucleus
    • ensures adequate cellular levels of T3 w/in CNS
    • very sensitive to changing circulating levels of T4
      • low levels of T4 ↑ [5’-deiodinase]
      • high levels of T4 ↓ [5’-deiodinase]
109
Q

5-deiodinase

A

removes the I at position 5 to convert it into rT3 & inactivate it

  • removes circulating TH when excess (removes possibility of converting T4 ➔ T3
  • highly expressed in fetal tissues, placenta, CNS
    • placenta = filter btwn mother & fetus
  • inactivates T4 by conversion to rT3
  • inactivates T3 by conversion to T2 (no 5’ or 5 I)
  • ↑ in hyperthyroidism
  • ↓ in hypothyroidism
110
Q

TH actions on fetal development

A
  • roles in terminal differentiation of brain cells & neural development
    • mostly mediated by TR⍺ → critical for life
  • development of the auditory system
    • human TH resistance syndrome (Refetoff syndrome) = mutation in TRβ ➔ deafness
    • congenital hypothyroidism = genetic/iodine deficiency
      • impairs terminal differentiation process ➔ severe mental & growth retardation
      • cretinism = most severe form of mental retardation caused by congenital hypothyroidism
  • development of sensory systems (auditory, visual)
  • neurogenesis
  • neural transmission (myelin sheath formation)
111
Q

cretinism

A

most severe form of mental retardation caused by congenital hypothyroidism

112
Q

TH actions on metabolism & thermogenesis

A
  • stimulates protein expression & turnover
  • ↑ metabolism secondary to thermogenesis (↑ basal body temp)
  • stimulate expression of β-adrenergic receptors & G-proteins to enhance actions of EPI (↑ adrenergic activity in general)
  • net result: ↑ BMR accompanied by ↑ energy expenditure & ↑ need for O2 in tissues to support ↑ activity
113
Q

TH actions to meet ↑ O2 requirements

A
  • enhances O2 absorption by resp system
  • ↑ expression of erythropoietin to enhance RBC production
  • enhances β-adrenergic receptor-mediated effects in the heart (inotropic & chronotropic effects)
114
Q

TH actions to meet ↑ energy requirements

A
  • ↑ GI motility tract
  • ↑ GI absorption efficiency
  • stimulate lipolysis
  • ↑ appetite ➔ stimulate CNS satiety/hunger centers
    • POMC neurons in Arc use ⍺MSH to signal PVN to secrete TRH & begin TH cascade
    • insulin & leptin inform brain that body has enough nutrients to ↑ metabolic rate
      • leptin produced by adipocytes ➞ ↑ adipocytes = ↑ leptin circulating = sufficient fat storage
      • insulin produced in response to food (during absorptive state) ➞ informs brain that body has food
115
Q

key points from the article

A
  • TH enhances adrenergic stimulation of brown adipose tissue by ↑ expression of genes coding for proteins that enhance the response to β3 stimulation
  • subsequent increase in cAMP ↑ D2 activity & ∴ intracellular T3
  • TH & SNS synergistically ↑ brown adipose tissue thermogenesis & adrenergic activation of brown adipose tissue enhances intracellular D2 activity
  • higher thermogenic capacity in hibernation season
  • HPT-axis & HPT enhance thermogenic capacity
116
Q

BAT

A

brown adipose tissue

  • rich in mitochondria ➞ gives brownish color
  • more efficient at using uncoupling proteins
  • site of non-shivering thermogenesis
117
Q

TH actions on thermogenesis

A

non-shivering thermogenesis by UCP1 (uncoupling proteins) in mitochondria of brown adipose tissue

  • UCP1: brown adipose tissue (BAT)
  • UCP3: muscle
  • located in inner mitochondrial membrane
  • redirect H+ flow from the ATPase (final step of the respiratory chain) ➞ dissipates energy in the form of heat instead of ATP
118
Q

hypothyroidsm symptoms

A
  • tiredness
  • weakness
  • fatigue
  • bradycardia
  • cold intolerance
  • constipation
  • mental impairment
  • depression
  • weight gain
  • muscle cramps
  • infertility
  • goiter (if primary hypothyroidism)
119
Q

hypothyroidism

A

thyroid gland is not producing sufficient TH

  • anabolic state
  • ↓ T4 w/ low-high levels of TSH
  • ↓ levels of 5-deiodinase
120
Q

hypothyroidism therapy goal

A

replace T4 to mimic normal physiological levels & attain normal TSH levels

121
Q

hashimoto’s disease

A

autoimmune hypothyroidism: body produces antibiodies against TPO, Tg, & TSHR

  • progressive destruction of the thyroid gland
  • symptoms: fatigue, weight gain, joint/muscle pain, feeling cold, bradycardia, slow metabolism
  • may present w/ goiter
122
Q

hyperthyroidism

A

overproduction of TH

  • body is in catabolic state
  • ↑ 5-deiodinase
  • ↑ T4 w/ low-high levels of TSH
123
Q

hypothyroidism dx

A
  • hx
  • ↓ T4 w/ low-high levels of TSH
  • test for specific autoimmune antibiodies
124
Q

hyperthyroidsim symptoms

A
  • nervousness
  • fatigue
  • tachycardia
  • palpitations
  • weight loss
  • heat intolerance
  • irritability
  • muscle weakness
  • tremor
  • sleep disturbance or insomnia
  • ↑ perspiration
  • ↑ GI motility
  • goiter if TG is overstimulated
125
Q

hyperthyroidism dx

A
  • hx
  • ↑ T4 w/ low-high levels of TSH
126
Q

hyperthyroidism tx

A
  • surgery
  • antithyroid rx: adjuvant therapy w/ no specific effect on TG can be useful to control peripheral manifestations of thyrotoxicosis (e.g. β-blockers)
127
Q

grave’s disease

A

continuous activation of TSHR by antibodies

  • autoimmune hyperthyroidism
  • LATS: long-acting thyroid stimulating antibody
  • symptoms consistent with hyperthyroidism: insomnia, weight loss, heat intolerance, tachycardia, exopthalmos
  • commonly presents with goiter
128
Q

hibernation

A

strategy to conserve energy by decreasing thermogenesis/metabolic activity & lower energy

  • episodes of torpor & euthermia (wake up for ~15h)
129
Q

what happens during pre-hybernation

A

thyroid activity ↑ → TH ↑

130
Q

during torpor

A
  • ↑ levels of albumin (main TH carrier proteins in blood → more can be bound: inactive & ready)
  • ↑ availability in D2 (intracellular conversion of T4 → T3)
  • NE-mediated by β-adrenergic receptors stimulates D2
  • TH ↑ expression of UCP1
  • more expression of β-adrenergic receptors in BAT
  • TH & SNS synergistically ↑ brown adipose tissue thermogenesis & adrenergic activation of brown adipose tissue enhances intracellular D2 activity
  • higher thermogenic capacity
131
Q

iodination of TG

A
  • iodination occurs at apical colloid border
  • iodination of the tyrosyl residues (iodotorosines) forms monoiodotyrosine (MIT) & diiodotyrosine (DIT)
    • these are coupled to form T3/T4
  • iodide must be oxidized by TPO to be able to iodinate tyrosine residues
132
Q

D1 5’-deiodinase

A
  • kidney, liver, skeletal muscle (& small amount in the thyroid gland)
  • 5’ monodeiodination forms T3 ➞ active form
  • most abundant
  • in PM of cells ➞ ensures adequate circulating levels of T3
133
Q

D2 5’-deiodinase

A
  • brain & pituitary gland
  • in ER close to nucleus
  • ensures adequate cellular levels of T3 w/in CNS
  • very sensitive to changing circulating levels of T4
    • low levels of T4 ↑ [5’-deiodinase]
    • high levels of T4 ↓ [5’-deiodinase]

NPB 130 (5 decks)

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