ST-2

• Second messengers


  cAMP, cGMP and NO
• Regulation of Protein kinase A (PKA, cAMP-dependent protein kinase) by cAMP (cyclic AMP)


  1. PKA

  2. cAMP dependent cascade of regulation of glycogen metabolism

  3. Adenylyl cyclase and cAMP mediated pathway in regulation of gene expression

  
• CREB-cAMP response element-binding protein

  CBP- CREB-binding protein
• Hormone-induced activation and inhibition of adenylyl cyclase in adipose tissue

  Hormones acting via Adenylyl Cyclase

  
• Soluble Guanylyl cyclase and Receptors of Atrial natriuretic peptide (ANP) (NPRA and NPRB) with guanylyc cyclase activity


  • NPRA and NPRB - receptors of Atrial natriuretic peptide (ANP) with guanylyl cyclase activity
  • Receptors for Atrial natriuretic peptide (ANP) are 3 types: NPRA, NPRB and NPRAC
  • NPRA are NPRB are linked to guanylyl cyclases
  • cGMP stimulate cGMP-dependent protein kinase (PKG), which will then induce smooth muscle relaxation
  • NPRC is G-protein-linked and is a "clearance receptor" that acts to internalise and destroy the ligand

  
• Protein kinase G (PKG)


  • PKG stimulates directly: 1. Synthesis of NO (stimulates NOS III or eNOS) 2. Soluble intracellular Guanylyl cyclase (sGC)
  • PKG inhibits phospodiesterase 5 (PDE5), which selectively cleavages cGMP
  • PKG also modulates the intracellular concentration of Са2+, which is a key ion for activity of NOS-III (eNOS) and NOS-I (nNOS). PKG modulats the Са2+-АTPase, the L-type calcium cannels and etc.

  
• Cyclic GMP induces smooth muscle relaxation by multiple mechanisms

  1. Phosphorylation and inhibition of Voltage-gated Ca2+ (decrease intracellular Ca2+)

  2. Phosphorylation and inhibition of IP3-mediated release of Ca2+ from ER

  3. Activates K+ channels, which leads to hyperpolarization and relaxation

  4. Phosphorylates and activates myosin light chain phosphatase, the enzyme that dephosphorylates myosin light chains, which leads to smooth muscle relaxation
• cGMP in the process of vision

  • Rhodopsin and cGMP phosphodiesterase
  • In dark-adapted rod cells, a high level of cGMP keeps nucleotide-gated nonselective cation channels open
  • Light absorption generates activated opsin, O*, which binds inactive GDP-bound Gt protein and mediates replacement of GDP with GTP
  • The free Gta·GTP activates cGMP phosphodiesterase (PDE) that converts cGMP to GMP
  • The resulting decrease in cytosolic cGMP leads to dissociation of cGMP from the nucleotide-gated channels in the plasma membrane and closing of the channels
  • Closing of the channels leads further to membrane hyperpolarization – leading to generation of action potential

  
• Phosphodiesterases (PDEs)


  • Catalyze hydrolysis of cAMP (to AMP) and cGMP (to GMP)
  • Superfamily consists of 11 members differentiated by cAMP/cGMP substrate specificity
  • cGMP is the sole substrate of PDEs 5, 6, and 9, and is a dual substrate (with cAMP) of PDEs 1, 2, 3, 10, and 11
  • cAMP is the sole substrate of PDEs 4, 7, and 8

  
• cGMP action on vascular function gets mediated through its activation of PKGs balanced by the inactivating PDEs
• Effects on vascular proliferation are unclear, with studies suggesting both pro and anti-proliferative effects depending on activation (receptor GC vs. soluble GC), location, and quantity of intracellular cGMP

  
• Different, but complementary, effects on inflammatory modulators depending on the activating source
• Effects in neurological function, most notably regarding synaptic plasticity and memory formation and retrieval
• Effects on metabolic homeostasis - positive changes in energy expenditure
• In brown adipose tissue increases the quantity, size, and activity of mitochondria
• Induce the browning of white adipose cells and exert similar effects on mitochondria in other cells throughout the body
• Improves insulin sensitivity in white adipose cells
• Regulates (suppresses) glucagon release in the endocrine pancreas
• Exerts antioxidant and anti-inflammatory effects in the liver
• Regulates food and water intake through interactions in the hypothalamus