The pivotal role of phosphoinositide-3 kinase in the human somatostatin sst(4) receptor-mediated stimulation of p44/p42 mitogen-activated protein kinase and extracellular acidification

Biochem Biophys Res Commun. 1999 Sep 16;263(1):239-43. doi: 10.1006/bbrc.1999.1351.

Abstract

We have previously demonstrated in CHO-K1 cells expressing recombinant human sst(4) receptors that somatostatin-induced increases in extracellular acidification are susceptible to a marked desensitisation after pretreatment with somatostatin, but not the somatostatin analogue, L-362855. In the present study, we have examined the human sst(4) receptor-mediated stimulation of p44/p42 mitogen-activated protein (MAP) kinase to determine whether this response is susceptible to a similar agonist-specific desensitisation. Western analysis using phosphospecific antibodies revealed that both somatostatin and L-362855 induced a transient stimulation of MAP kinase which could be desensitised by pretreatment with somatostatin, but not L-362855. The selective phosphoinositide (PI) 3-kinase inhibitor, LY 249002, blocked both the somatostatin-induced increase in MAP kinase phosphorylation and extracellular acidification. However, the MEK1 inhibitor, PD 98059, blocked only the sst(4) receptor-mediated stimulation of MAP kinase and not the extracellular acidification response. In summary, the human sst(4) receptor is selectively desensitised by somatostatin and not by L-362855 and signals through two different PI 3-kinase linked pathways.

MeSH terms

  • Animals
  • CHO Cells
  • Calcium-Calmodulin-Dependent Protein Kinases / metabolism*
  • Chromones / pharmacology
  • Cricetinae
  • Enzyme Inhibitors / pharmacology
  • Extracellular Space / metabolism
  • Humans
  • Hydrogen-Ion Concentration
  • Membrane Proteins
  • Mitogen-Activated Protein Kinase 1 / metabolism*
  • Mitogen-Activated Protein Kinase 3
  • Mitogen-Activated Protein Kinases*
  • Morpholines / pharmacology
  • Peptides, Cyclic / pharmacology
  • Phosphatidylinositol 3-Kinases / metabolism*
  • Phosphoinositide-3 Kinase Inhibitors
  • Phosphorylation
  • Receptors, Somatostatin / genetics
  • Receptors, Somatostatin / metabolism*
  • Recombinant Proteins / genetics
  • Recombinant Proteins / metabolism
  • Somatostatin / analogs & derivatives
  • Somatostatin / pharmacology

Substances

  • Chromones
  • Enzyme Inhibitors
  • L 362855
  • Membrane Proteins
  • Morpholines
  • Peptides, Cyclic
  • Phosphoinositide-3 Kinase Inhibitors
  • Receptors, Somatostatin
  • Recombinant Proteins
  • somatostatin receptor subtype-4
  • 2-(4-morpholinyl)-8-phenyl-4H-1-benzopyran-4-one
  • Somatostatin
  • Calcium-Calmodulin-Dependent Protein Kinases
  • Mitogen-Activated Protein Kinase 1
  • Mitogen-Activated Protein Kinase 3
  • Mitogen-Activated Protein Kinases