Flashcards in Unit 6 - Growth Hormone Deck (43)
GH structure, and halflife
single chain polypeptide with 20 minute halflife
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
role of GHRH on GH
-increases GH gene transcription
-promotes GH release
-stimulates production of GHRH receptor
-stimulates somatostatin release
role of somatostatin on GH
-decreases pulse frequency
-decreases pulse amplitude
-no impact on GH synthesis
-inhibits GHRH release
what is ghrelin more important for, other than GH secretion control?
feeding behavior, energy regulation, and (possibly) sleep
-target for anti-obesity drugs
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
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
what is GH secretion stimulated by?
sex steroids (growth sputs at puberty)
fasting/hypoglycemia (used as clinical test to provoke GH secretion if suspect deficiency)
AA (decrease somatostatiin release)
dopamine aconists (suppressed in acromegaly)
what is GH secretion inhibited by?
how does obesity VS fasting affect GH?
obesity decreases number and duration of each pulse
fasting increases number and amplitude of each pulse
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
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)
what causes short stature in Pygmies?
severe underexpression of GH receptor
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
what are the effects of GH on muscle?
increased glucose and AA uptake
increased PRO synthesis
what are GH effects on chondrocytes?
increased AA uptake, PRO synthesis, DNA/RNA synthesis, chondroitin sulfate, collagen, cell size and number
what are GH effects on brain?
affects mood and behavior
effects of GH on liver
stimulates IGF-1 production, and stimulates hepatic glucose production
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
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
what happens if there's GH without insulin?
GH doesn't induce growth
-also won't stimulate growth w/o CHO
how does IGF-1 act?
stimulates growth via endocrine, paracrine, and autocrine fashion
-negative FB to hypothalamus and pituitary to down-regulate GH secretion
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
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
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
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
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
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
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