Unit 6 - Growth Hormone Flashcards Preview

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Flashcards in Unit 6 - Growth Hormone Deck (43)
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1

GH structure, and halflife

single chain polypeptide with 20 minute halflife

2

how is GH regulated?

hypothalamus: GHRH (activate) and somatostatin (inhibits)
stomach/pancreas: ghrelin (unknown how activates, but acts as segretagogue receptor)

all go to GPCRs, but integration leads to episodic, pulsatile secretion

3

role of GHRH on GH

-increases GH gene transcription
-promotes GH release
-stimulates production of GHRH receptor
-stimulates somatostatin release

4

role of somatostatin on GH

-decreases pulse frequency
-decreases pulse amplitude
-no impact on GH synthesis
-inhibits GHRH release

5

what is ghrelin more important for, other than GH secretion control?

feeding behavior, energy regulation, and (possibly) sleep
-target for anti-obesity drugs

6

pulsatile nature of GH over lifespan

pulses primarily at night
-number stays nearly constant, but larger amplitude during puberty
-strenous exercise causes surge in GH

7

how does Ritalin (and other sleep-disrupting drugs) affect growth?

1 inch shorter and 4 pounds lighter than peers
-can catch up if good nutrition maintained

8

what is GH secretion stimulated by?

deep sleep
exercise
sex steroids (growth sputs at puberty)
fasting/hypoglycemia (used as clinical test to provoke GH secretion if suspect deficiency)
AA (decrease somatostatiin release)
stress
alpha-adrenergic agonists
dopamine aconists (suppressed in acromegaly)

9

what is GH secretion inhibited by?

IGF-1
obesity
glucocorticoids (cortisol)
hyperglycemia
FFA
GH
beta-adrenergic agonists

10

how does obesity VS fasting affect GH?

obesity decreases number and duration of each pulse

fasting increases number and amplitude of each pulse

11

how is GH related to somatostatin and IGF-1?

hypothalamus releases somatostatin and GHRH
-somatostatin inhibits, while GHRH stimulates GH secretion (both via GPCR; stimulate with AC, cAMP, PKA, and Ca++)
-GH inhibits GHRH release, and stimulates somatostatin release, then acts on liver to release IGF-1
-IFG-1 stimulates target tissue effects, stimulates somatostatin release, and inhibits GHRH release and anterior pituitary activity

12

how does GH activate its receptor?

transmembrane receptor in cytokine receptor family to activate JAK/STAT pathway
-causes dimerization for signal transduction, and binding to 1+ JAK tyrosine kinases 1
-induces phosphorylation of JAK kinases and receptor 2, then STATs dimerize and translocate to nucleus to act as transcription activators
-increased expression of CISH (GH target gene)
-major sites of action are bone, liver, and adipocyte (but also kidney, muscle, eye, brain, heart, and immune cells)

13

what causes short stature in Pygmies?

severe underexpression of GH receptor

14

what are the effects of GH on adipose tissue?

decrease glucose uptake and increase lipolysis
-stimulated release and oxidation of FFA, especially during fasting
-decreased LPL activity
-decreased lipogenesis

15

what are the effects of GH on muscle?

increased glucose and AA uptake
increased PRO synthesis

16

what are GH effects on chondrocytes?

increased AA uptake, PRO synthesis, DNA/RNA synthesis, chondroitin sulfate, collagen, cell size and number

17

what are GH effects on brain?

affects mood and behavior

18

effects of GH on liver

stimulates IGF-1 production, and stimulates hepatic glucose production

19

effects of GH on bone

affects all phases and zones of GH
-supports differentiation of mesenchymal stem cells (prechondrocytes) into chondrocytes
-local IGF-1 induces clonal expansion of early chondrocytes and maturation of later chondrocytes
-leads to synthesis of ECM proteins like collagen II, hyaluronic acid, and mucopolysaccharides
-as cells move closer to already-formed trabecular bone, it becomes calcified and remodeled by osteoclasts and osteoblasts to form mature bone

20

where is IGF-1 made and what are its levels?

some is from kidney/skin, but mostly is liver
-circulates all day long at relatively constant level
-inhibited by anorexia and other eating disorders

21

what happens if there's GH without insulin?

GH doesn't induce growth
-also won't stimulate growth w/o CHO

22

how does IGF-1 act?

stimulates growth via endocrine, paracrine, and autocrine fashion
-negative FB to hypothalamus and pituitary to down-regulate GH secretion

23

how is IGF-1 used clinically?

primary screening test when considering GH deficiency, since its levels in circulation are more stable and reflective of GH levels in normal individuals

24

how do insulin, IGF-1, and IGF-II differ?

insulin, IGF-I and IGF-II share 3 domains (A, B, and C) with high degree of AA sequence homology
-C region is cleaved from insulin (C-peptide), but not IGFs
-IGFs also have short D domain
-IGF-II secretion not significantly regulated by GH
-insulin and IGF-I are heterotetramers joined by DS bonds, with cytoplasmic beta units with tyrosine kinase domains and autophosphorylation sites
-IGF-II receptor (also M6P receptor) is single polypeptide chain w/o kinase domain, and poorly understood cellular function

25

how are signaling pathways activated by IGF-1?

dimerization of IGF-1 receptors leads to autophosphorylation
-recruits 2 major phosphotyrosine binding PRO (IRS-1 and Shc) which are phosphorylated by IGF-1 receptor
-recruits other PRO to membrane, leading to activation of phosphoinositol-3-kinase and Ras/MAP kinase pathways that regulate cellular transcription

26

when does the pubertal growth spurt happen?

peak rate of growth corresponds to peak serum concentrations of IGF-1
-both sex hormones contribute to rapid increase
-in girls, begins at early puberty
-in boys, occurs after puberty has begun

27

what are some causes of GH deficiency?

organic: congenital absence of pituitary stalk, TBI, or cranial radiation therapy
idiopathic: functional of developmental state, which resolves in mid-puberty

28

can mutations in GH-1 gene be treated with rhGH?

no, because the individual will eventually make Abs VS what is perceived as a foreign PRO

29

what happens if you give extra GH in excess of normal during treatment of GH deficiency?

nothing; it doesn't increase the rate of growth above what is normal

30

Laron syndrome

autosomal recessive point mutation or deletion in GH receptor (heterozygotes have mild growth retardation)
-markedly low IGF-1
-normal or elevated GH concentration (unable to respond to it)
-severe post-natal growth failure
-treatable with rhIGF-1 before puberty, but not rhGH
-similar if have mutation of Stat5b gene

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