Biochemistry of pituitary hormones Flashcards
What is growth hormone known for?
The primary hormone responsible for body growth
What happens if individuals do not make enough GH or have defective GH receptors?
They are short-statured
What is the other role of GH?
Regulate carbohydrate, protein, and lipid metabolism. For instance, GH decreases fat and increases lean body mass
What is the anterior pituitary a site for?
Synthesis of several hormones
How are most anterior pituitary hormones synthesized?
By somatotropic cells located in the anterior pituitary gland, regulated by protein, POU1F1
How is acromegaly caused?
By pituitary tumors secreting excess growth hormone, over 95% of patients with acromegaly harbor a GH-secreting pituitary adenoma
What is acromegaly charcterised by?
Elevated levels of GH and Insulin-like growth factor 1 (IGF-1)
What controls the secretions of GH?
- Somatostatin
- Ghrelin
- GH-releasing hormone
- Somatotroph-specific transcription factors (POU1F1)
- Insulin-like growth factor 1
How does IGF-1 control the synthesis and secretion of GH?
Through negative feedback control
Where is somatostatin produced?
In neurons of the ventromedial nucleus of the hypothalamus
What is the function of somatostatin?
Inhibition of GH secretion via a G protein-coupled somatostatin receptor on somatotrophs
When are somatostatin analogs the treatment of choice?
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
What happens if SSA therapy is discontinued?
Recurrence will be present in 56% of cases after 12 to six 233ks of treatment withdrawal
What is Ghrelin?
A neuroendocrine peptide hormone that plays a role in important biological processes, such as growth hormone secretion and food intake
Which cells produce Ghrelin?
Mainly produced in the cells of the stomach but also in the ventromedial and arcuate nucleus of the hypothalamus
How does Ghrelin work?
It stimulated GH secretion through its GH surface receptor (GHS-1aR), a GPCRq, to increase intracellular Ca2+ –> IP2 signal transduction pathway
Where is GHRH expressed?
In the arcuate nucleus of the hypothalamus
Where does GHRH exert its effect and what is it?
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
What regulates protein kinase?
cAMP, the binding of 4 cAMP molecules activates the protein kinase by freeing catalytically active subunit
What does a mutation in GHRH cause?
Severe growth hormone deficiency in humans
What is growth hormone?
A single chain polypetide with a molecular mass of 21500 Da that contains 191 amino acids
What other hormone is Growth hormone structurally similar to?
Structurally similar to prolactin and placental hormone chorionic somatomammotropin, it has overlapping biological effects
What is the overall structure of Growth hormone similar to?
Similar to a group of cytokines, hormones, interleukins, and interferons
How is GH synthesized?
By somatotropic (acidophilic) cells of adenohypophysis and stored within intrcellular granules
What are the targets of GH?
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
How id the GH effect mediated?
Mediated through its receptor, GHR, a transmembrane glycoprotein
What is GHR a member of?
GHR is a member of the class 1 hematopoietic cytokine receptor family which includes prolactin, erythropoitein and leptin receptors
What is the GH receptor family like?
It lacks intrinsic kinase activity and relies on associated tyrosine kinases for signal transduction following ligand binding
What is GHR like?
It exists as a homodimer in its non-ligates state and each GHR monomer is associated with one or more inactive kinase
What is the GHR signaling pathway like?
Signals through he JAK2 pathway, but can also activate downstream signaling via other non-receptor tyrosine kinases belonging to the SRC family kinases
What is the GH intracellular signal transduction like?
- GH binding induces a conformational change in the constitutive dimer of GHR, locking together the extracellular receptor-receptor interaction domain
- The interaction leads to the activation of several intracellular signaling pathways
What are the examples of intracellular signaling pathways that are activated because of GH?
The JAK/STAT pathway
The MAPK/ERK pathway
What is the most direct route of GH intracllular transduction?
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
What is the JAK/STAT signaling pathway?
Activation of the tyrosine kinase of the JAK family (predominantly JAK2) leads to the activation of STAT proteins (particularly STAT5b)
When do JAKs become activated?
Only when they associate ligand-occupied cytokine receptors like GHR
What does JAK2 phosphorylate?
Often phosphorylates tyrosine residue both on intracellular domain of the receptor and on itself
What does the phosphorylated site of JAK/STAT signaling pathway act as?
Acts as a recognition site for the binding of other proteins, such as the SH2-interaction domain
What kind of JAK do GH-receptors recruit?
JAKs which phosphorylate the receptors to generate binding sites for gene regulatory proteins
What is STAT?
Important gene regulator protein, unphosphorylated cytosolic monomers and recruited by JAKs
What is the result of subsequent tyrosine phosphorylation by activated JAKs?
Dimerization –> which results in translocation of the complex to the nucleus and association with other regulatory proteins
What happens to the activated STAT5 dimer?
It gets translocated to the nucleus where it binds to DNA and acts as a transcription factor cause gene expression
What is the result of patients with a mutation in STAT5b?
Severe postnatal growth failure
What kind of mutation is Laron syndrome?
Loss of function mutation, GHR mutations in the extracellular, transmembrane and intracellular regions which cause the autosomal recessive and GH insensitive sydnrome
What is Laron syndrome?
A growth disorder due to insensitivity to GH caused by a mutation in the GHR
What is Laron syndrome associated with?
Growth retardation, and patients are typically > 5sD below normal adult height
How is Laron syndrome defined?
An elevated level of baseline serum GH but low circulating concentrations of IGF-1 and IGF-binding protein 3
What is the main pathway in the liver, with respect to growth?
Activation of the JAK and signal transducer and activator of transcription 5B (STAT 5B)
What does the activation of the JAK2/STAT5lead to (in terms of genes)?
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
What do the IGFBPs bind to?
Bind to IGFs, preventing them from being degraded and facilitating their transport through body compartments
How do IGF1, IGF2, IGFBP3, and ALS enter the circulation?
In the form of ternary complex
What happens to IGF1 and IGF2 in the ternary complex?
They are liberated from this ternary complex by proteases, notably PAPPA2, which enables them to pass through the capillary epithelium and enter the interstitium
What does circulating IGF-1 serve as?
Serves as a negative factor for GH secretion in the pituitary gland and has a general anabolic function on almost all cell types
What is IGF1?
The mediator of the anabolic and mitogenic activity of GH
What family are IGF1 and IGF2 part of?
Members of a family of insulin-related peptides
How can IGF1 bind to insulin receptor (even at low affinity)?
The structural similarity of IGF-1 to insulin
Where is IGF-1 secreted?
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
What are the key components required for postnatal growth?
IGF-1
IGFBP3
ALS
–> All are GH-dependent
What are the functions of insulin-like growth factors?
Cell proliferation, promote tissue-specific cell functions,
Exert metabolic effects similar to insulin and evoke anti-apoptotic actions
What do IGF-1 and IGF-2 stimilate?
The chondrocytes in the epiphyseal plate
How does IGF-1 exert its effects?
Via activation of the IGF-1 receptor
What is the biochemical structure of the IGF-1 receptor similar to?
Other growth factor receptors and the insulin receptor
In which cases is IGF-1 highly overexpressed?
In most malignant tissues, where it functions as an anti-apoptotic agent by enhancing cell survival
What does the ligand binding to the receptor alpha subunit lead to? (IGF-1)
Triggers a conformational change in the receptor, leading to receptor autophosphorylation and tyrosine phosphorylation of multiple adaptor proteins
Where are the chondrocytes found?
In the epiphyseal plate and they are directly stimulated by GH
What do proliferative and hypertrophic chondrocytes secrete?
IGFs (autocrine reglation)
What are the effects of GH excess in adults?
Insulin resistance and hyperglycemia because of GH’s anti-inuslin actions
What does the reduction of elevated GH levels in patients with acromegaly lead to?
Reduction of elevated GH levels by pegvisomant results in marked improvement in carbohydrate metabolism and diabetic state
What is pegvisomant?
A GH antagonist
What is the effect of IGF1 in muscle?
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
What are the effects of GH and IGF1 on carbohydrate metabolism?
Opposite effects from each other:
–> GH: generally raises glucose levels and promotes insulin resistance
–> IGF1: lowers glucose levels and increases insulin sensitivity
What are the effects of GH on lipid metabolism?
GH is a lipolytic hormone and affects both lean mass and fat mass
How does GH express its effects in terms of lipid metabolism?
Exerts its biological effect through transcriptional regulation and acute changes in the catalytic activity of several enzymes
What are the mechanisms by which GH leads to increased lipolysis?
Involves the expression of the β-3 adrenergic receptor
How are the lipolytic effects of β-3 adrenergic receptors mediated?
Via G-protein-coupled adenylate cyclase, cAMP, and protein kinase A, followed by phosphorylation and activation of hormone-sensitive lipase
