Somatostatin Receptors

Question 1

Somatostatin background (5)

Answer 1

• Discovered in 1973 from hypothalamic extract – Salk Institute @ La Jolla
• Encoded by chromosome 3q28
• Produced as preprosomatostatin then cleaved
• Expressed in brain
• Somatostatin interneurons + hypothalamus – inhibits neuronal firing
• Pancreas – delta cells – inhibits insulin and glucagon secretion
• GI tract – inhibits secretion of gastrin, secretin, cholecystokinin and vasoactive intestinal peptide (= ↓acid secretion from the stomach)
• Half-life = 3 minutes(!)

THE ANTI-HORMONE HORMONE

Question 2

Somatostatin Receptors background (4)

Answer 2

• 5 Somatostatin Receptors (SSTR)
  -SSTR1-5
• SSTR2 = SSTR2a/2b only receptor w/ a subtype
• Encoded by 5 different genes
• Anti-secretory functions mediated by 2nd messenger systems
• cAMP, activation of ion channels

Question 3

SSTRs info. continued (3)

Answer 3

GPCRs – expressed in
* CNS
* Gut
* Pancreas
* Pituitary
* Kidney
* Thyroid,
* Lung
* Immune Cells

• Additional level of regulation
• Homo and heterodimerization occurs
• Heterodimers with
  –dopamine Rs
  –Opioid Rs
  –Epidermal growth factors
• = Receptor complexes with unique pharmacological properties

Question 4

Explain the Intracellular signalling of SSTRs (5)

Answer 4

• Decrease cAMP production
• All 5 SSTRs activate protein tyrosine
  phosphatases including
• SH2 domain-containing cytosolic tyrosine
  phosphatases (SHP-1/SHP-2)
• Can also couple to protein serine/threonine
  phosphatase 2A and 2B (PP2A and PP2B)
• Therefore, inhibition occurs by:
• Receptor dephosphorylation OR
• Inhibition of MAPK signalling (ERK1/2) AND/OR
• PI3K/Akt signaling
• Activation of K+ channels → inactivation of Ca2+channels (hyperpolarisation)

Question 5

Inhibition of electrical activity by SSTR agonism (3)

Answer 5

images - Mediated by activation of a K+ channel

Hippocampal Neuron
vs
Pancreatic Alpha Cell

Question 6

Consequences of SSTR activation (6)

Answer 6

1) SSTR Activation

2a) ↓Hormone secretion
2b) ↓Cell growth (cell cycle arrest)
2c) ↑Apoptosis

3a) i.e. IGF1/IGF2/EGF/insulin

= Useful for suppression of unwanted cell growth = tumors

Question 7

What are the most common sites of Neuroendocrine Tumors? (5)

Answer 7

• GI tract (+ digestive system = 60%)
• Pancreas (+ digestive system = 60%)
• Lungs (20-30%)
• Adrenal Glands
• Typically results in hormonal hypersecretion
  i.e. glucagonoma
• Around 80% of neuroendocrine tumors express SSTRs, typically SSTR2

Question 8

Name some Somatostatin analogues (6)

Answer 8

• Octreotide
• Lanreotide
• Vapreotide
• Seglitide
• Pasireotide

they have a half life of 0.5-12hrs

Question 9

How are somatostatin analogues delivered? (3)

Answer 9

Depending on drug preparation they
can be administered:

• 2-3 daily by sub-cutaneous injection
• Continuous slow infusion over several
  hours
• Slow release intramuscular injection
  (every 10-28 days)

Question 10

Why are SST analogues used?

Answer 10

Radiolabelled SST analogues have been used to detect primary tumors and malignancies – however, clinical utility still debated

Question 11

Somatostatin analogues – mechanisms
overview (5)

Answer 11

direct mechanisms:

a) inhibition of cell cycle progression
b) inhibition of growth factor effects
c) induction of apoptosis

2ba) inhibition of growth factor release
2bb) inhibition of growth factor signalling

Question 12

Mechanisms of tumor suppression (3)

Answer 12

• Inhibition of cell cycle progression
• Reduction in cyclin D1 expression –synthesised during G1 phase
• Inhibition of growth factor signalling