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Endocrine System > Biochemistry of pituitary hormones > Flashcards

Biochemistry of pituitary hormones Flashcards

1
Q

What is growth hormone known for?

A

The primary hormone responsible for body growth

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2
Q

What happens if individuals do not make enough GH or have defective GH receptors?

A

They are short-statured

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3
Q

What is the other role of GH?

A

Regulate carbohydrate, protein, and lipid metabolism. For instance, GH decreases fat and increases lean body mass

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4
Q

What is the anterior pituitary a site for?

A

Synthesis of several hormones

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5
Q

How are most anterior pituitary hormones synthesized?

A

By somatotropic cells located in the anterior pituitary gland, regulated by protein, POU1F1

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6
Q

How is acromegaly caused?

A

By pituitary tumors secreting excess growth hormone, over 95% of patients with acromegaly harbor a GH-secreting pituitary adenoma

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7
Q

What is acromegaly charcterised by?

A

Elevated levels of GH and Insulin-like growth factor 1 (IGF-1)

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8
Q

What controls the secretions of GH?

A
  1. Somatostatin
  2. Ghrelin
  3. GH-releasing hormone
  4. Somatotroph-specific transcription factors (POU1F1)
  5. Insulin-like growth factor 1
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9
Q

How does IGF-1 control the synthesis and secretion of GH?

A

Through negative feedback control

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10
Q

Where is somatostatin produced?

A

In neurons of the ventromedial nucleus of the hypothalamus

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11
Q

What is the function of somatostatin?

A

Inhibition of GH secretion via a G protein-coupled somatostatin receptor on somatotrophs

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12
Q

When are somatostatin analogs the treatment of choice?

A

Somatostatin Analogs are the treatment of choice when:
1. Surgery is not curative
2. It is not possible because the patient is not a candidate for surgery or
3. There is a very low possibility of a complete surgical resection
4. Patient refuses surgery

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13
Q

What happens if SSA therapy is discontinued?

A

Recurrence will be present in 56% of cases after 12 to six 233ks of treatment withdrawal

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14
Q

What is Ghrelin?

A

A neuroendocrine peptide hormone that plays a role in important biological processes, such as growth hormone secretion and food intake

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15
Q

Which cells produce Ghrelin?

A

Mainly produced in the cells of the stomach but also in the ventromedial and arcuate nucleus of the hypothalamus

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16
Q

How does Ghrelin work?

A

It stimulated GH secretion through its GH surface receptor (GHS-1aR), a GPCRq, to increase intracellular Ca2+ –> IP2 signal transduction pathway

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17
Q

Where is GHRH expressed?

A

In the arcuate nucleus of the hypothalamus

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18
Q

Where does GHRH exert its effect and what is it?

A

Exerts its effects on somatotroph proliferation and GH secretion via a G protein-coupled receptor, GHRHR, in the presence of pituitary-specific transcription factor POU1F1

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19
Q

What regulates protein kinase?

A

cAMP, the binding of 4 cAMP molecules activates the protein kinase by freeing catalytically active subunit

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20
Q

What does a mutation in GHRH cause?

A

Severe growth hormone deficiency in humans

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21
Q

What is growth hormone?

A

A single chain polypetide with a molecular mass of 21500 Da that contains 191 amino acids

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22
Q

What other hormone is Growth hormone structurally similar to?

A

Structurally similar to prolactin and placental hormone chorionic somatomammotropin, it has overlapping biological effects

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23
Q

What is the overall structure of Growth hormone similar to?

A

Similar to a group of cytokines, hormones, interleukins, and interferons

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24
Q

How is GH synthesized?

A

By somatotropic (acidophilic) cells of adenohypophysis and stored within intrcellular granules

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25
Q

What are the targets of GH?

A

Acts on multiple cell types, tissues and organs but for growth, its main targets are the liber and epiphyseal plated in long bones and spine

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26
Q

How id the GH effect mediated?

A

Mediated through its receptor, GHR, a transmembrane glycoprotein

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27
Q

What is GHR a member of?

A

GHR is a member of the class 1 hematopoietic cytokine receptor family which includes prolactin, erythropoitein and leptin receptors

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28
Q

What is the GH receptor family like?

A

It lacks intrinsic kinase activity and relies on associated tyrosine kinases for signal transduction following ligand binding

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29
Q

What is GHR like?

A

It exists as a homodimer in its non-ligates state and each GHR monomer is associated with one or more inactive kinase

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30
Q

What is the GHR signaling pathway like?

A

Signals through he JAK2 pathway, but can also activate downstream signaling via other non-receptor tyrosine kinases belonging to the SRC family kinases

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31
Q

What is the GH intracellular signal transduction like?

A
  1. GH binding induces a conformational change in the constitutive dimer of GHR, locking together the extracellular receptor-receptor interaction domain
  2. The interaction leads to the activation of several intracellular signaling pathways
32
Q

What are the examples of intracellular signaling pathways that are activated because of GH?

A

The JAK/STAT pathway
The MAPK/ERK pathway

33
Q

What is the most direct route of GH intracllular transduction?

A

Although many intracellular signaling pathways lead from sell-surface receptors to the nucleus, where they alter gene transcription, the JAK/STAT one is the most direct one

34
Q

What is the JAK/STAT signaling pathway?

A

Activation of the tyrosine kinase of the JAK family (predominantly JAK2) leads to the activation of STAT proteins (particularly STAT5b)

35
Q

When do JAKs become activated?

A

Only when they associate ligand-occupied cytokine receptors like GHR

36
Q

What does JAK2 phosphorylate?

A

Often phosphorylates tyrosine residue both on intracellular domain of the receptor and on itself

37
Q

What does the phosphorylated site of JAK/STAT signaling pathway act as?

A

Acts as a recognition site for the binding of other proteins, such as the SH2-interaction domain

38
Q

What kind of JAK do GH-receptors recruit?

A

JAKs which phosphorylate the receptors to generate binding sites for gene regulatory proteins

39
Q

What is STAT?

A

Important gene regulator protein, unphosphorylated cytosolic monomers and recruited by JAKs

40
Q

What is the result of subsequent tyrosine phosphorylation by activated JAKs?

A

Dimerization –> which results in translocation of the complex to the nucleus and association with other regulatory proteins

41
Q

What happens to the activated STAT5 dimer?

A

It gets translocated to the nucleus where it binds to DNA and acts as a transcription factor cause gene expression

42
Q

What is the result of patients with a mutation in STAT5b?

A

Severe postnatal growth failure

43
Q

What kind of mutation is Laron syndrome?

A

Loss of function mutation, GHR mutations in the extracellular, transmembrane and intracellular regions which cause the autosomal recessive and GH insensitive sydnrome

44
Q

What is Laron syndrome?

A

A growth disorder due to insensitivity to GH caused by a mutation in the GHR

45
Q

What is Laron syndrome associated with?

A

Growth retardation, and patients are typically > 5sD below normal adult height

46
Q

How is Laron syndrome defined?

A

An elevated level of baseline serum GH but low circulating concentrations of IGF-1 and IGF-binding protein 3

47
Q

What is the main pathway in the liver, with respect to growth?

A

Activation of the JAK and signal transducer and activator of transcription 5B (STAT 5B)

48
Q

What does the activation of the JAK2/STAT5lead to (in terms of genes)?

A

Leads to an increased expression of genes encoding:
1. IGF-1, IGF-2
2. IGFBP-3
3. IGFBP5
4. ALS (Acid labile subunit)
–> enter the circulation in the form of the so-called ternary complex

49
Q

What do the IGFBPs bind to?

A

Bind to IGFs, preventing them from being degraded and facilitating their transport through body compartments

50
Q

How do IGF1, IGF2, IGFBP3, and ALS enter the circulation?

A

In the form of ternary complex

51
Q

What happens to IGF1 and IGF2 in the ternary complex?

A

They are liberated from this ternary complex by proteases, notably PAPPA2, which enables them to pass through the capillary epithelium and enter the interstitium

52
Q

What does circulating IGF-1 serve as?

A

Serves as a negative factor for GH secretion in the pituitary gland and has a general anabolic function on almost all cell types

53
Q

What is IGF1?

A

The mediator of the anabolic and mitogenic activity of GH

54
Q

What family are IGF1 and IGF2 part of?

A

Members of a family of insulin-related peptides

55
Q

How can IGF1 bind to insulin receptor (even at low affinity)?

A

The structural similarity of IGF-1 to insulin

56
Q

Where is IGF-1 secreted?

A

Mainly by the liver and is transported to other tissues, acting as an endocrine hormone

–> Also secreted by other tissues, including cartilaginous cells, and acts locally as a paracrine hormone

57
Q

What are the key components required for postnatal growth?

A

IGF-1
IGFBP3
ALS
–> All are GH-dependent

58
Q

What are the functions of insulin-like growth factors?

A

Cell proliferation, promote tissue-specific cell functions,
Exert metabolic effects similar to insulin and evoke anti-apoptotic actions

59
Q

What do IGF-1 and IGF-2 stimilate?

A

The chondrocytes in the epiphyseal plate

60
Q

How does IGF-1 exert its effects?

A

Via activation of the IGF-1 receptor

61
Q

What is the biochemical structure of the IGF-1 receptor similar to?

A

Other growth factor receptors and the insulin receptor

62
Q

In which cases is IGF-1 highly overexpressed?

A

In most malignant tissues, where it functions as an anti-apoptotic agent by enhancing cell survival

63
Q

What does the ligand binding to the receptor alpha subunit lead to? (IGF-1)

A

Triggers a conformational change in the receptor, leading to receptor autophosphorylation and tyrosine phosphorylation of multiple adaptor proteins

64
Q

Where are the chondrocytes found?

A

In the epiphyseal plate and they are directly stimulated by GH

65
Q

What do proliferative and hypertrophic chondrocytes secrete?

A

IGFs (autocrine reglation)

66
Q

What are the effects of GH excess in adults?

A

Insulin resistance and hyperglycemia because of GH’s anti-inuslin actions

67
Q

What does the reduction of elevated GH levels in patients with acromegaly lead to?

A

Reduction of elevated GH levels by pegvisomant results in marked improvement in carbohydrate metabolism and diabetic state

68
Q

What is pegvisomant?

A

A GH antagonist

69
Q

What is the effect of IGF1 in muscle?

A

Direct effects on glucose uptake, it causes hypoglycemia despite a significant reduction in circulating insulin levels, which suggests IGF1 works directly through the IGF1R in muscle

70
Q

What are the effects of GH and IGF1 on carbohydrate metabolism?

A

Opposite effects from each other:
–> GH: generally raises glucose levels and promotes insulin resistance
–> IGF1: lowers glucose levels and increases insulin sensitivity

71
Q

What are the effects of GH on lipid metabolism?

A

GH is a lipolytic hormone and affects both lean mass and fat mass

72
Q

How does GH express its effects in terms of lipid metabolism?

A

Exerts its biological effect through transcriptional regulation and acute changes in the catalytic activity of several enzymes

73
Q

What are the mechanisms by which GH leads to increased lipolysis?

A

Involves the expression of the β-3 adrenergic receptor

74
Q

How are the lipolytic effects of β-3 adrenergic receptors mediated?

A

Via G-protein-coupled adenylate cyclase, cAMP, and protein kinase A, followed by phosphorylation and activation of hormone-sensitive lipase

75
Q
A

Endocrine System (25 decks)

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