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.
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.
Smalley
K S
KS
Department of Pharmacology, University of Cambridge, Tennis Court Road, Cambridge, CB2 1QJ, United Kingdom. wqq41014@glaxowellcome.co.uk
Feniuk
W
W
Sellers
L A
LA
Humphrey
P P
PP
D000818:Animals; D016466:CHO Cells; D017871:Calcium-Calmodulin-Dependent Protein Kinases / Q000378:metabolism*; D002867:Chromones / Q000494:pharmacology; D006224:Cricetinae; D004791:Enzyme Inhibitors / Q000494:pharmacology; D005110:Extracellular Space / Q000378:metabolism; D006801:Humans; D006863:Hydrogen-Ion Concentration; D008565:Membrane Proteins; D019950:Mitogen-Activated Protein Kinase 1 / Q000378:metabolism*; D048052:Mitogen-Activated Protein Kinase 3; D020928:Mitogen-Activated Protein Kinases; D009025:Morpholines / Q000494:pharmacology; D010456:Peptides, Cyclic / Q000494:pharmacology; D019869:Phosphatidylinositol 3-Kinases / Q000378:metabolism*; D000081082:Phosphoinositide-3 Kinase Inhibitors; D010766:Phosphorylation; D017481:Receptors, Somatostatin / Q000235:genetics / Q000378:metabolism*; D011994:Recombinant Proteins / Q000235:genetics / Q000378:metabolism; D013004:Somatostatin / Q000031:analogs & derivatives / Q000494:pharmacology
D017871:Calcium-Calmodulin-Dependent Protein Kinases; D002867:Chromones; D004791:Enzyme Inhibitors; D008565:Membrane Proteins; D019950:Mitogen-Activated Protein Kinase 1; D048052:Mitogen-Activated Protein Kinase 3; D020928:Mitogen-Activated Protein Kinases; D009025:Morpholines; D010456:Peptides, Cyclic; D019869:Phosphatidylinositol 3-Kinases; D000081082:Phosphoinositide-3 Kinase Inhibitors; D017481:Receptors, Somatostatin; D011994:Recombinant Proteins; D013004:Somatostatin; C091739:L 362855; C098681:somatostatin receptor subtype-4; C085911:2-(4-morpholinyl)-8-phenyl-4H-1-benzopyran-4-one