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 huma n sst(4) receptors that somatostatin-induced increases in extracellular aci dification are susceptible to a marked desensitisation after pretreatment w ith somatostatin, but not the somatostatin analogue, L-362855. In the prese nt study, we have examined the human sst(4) receptor-mediated stimulation o f p44/p42 mitogen-activated protein (MAP) kinase to determine whether this response is susceptible to a similar agonist-specific desensitisation. West ern analysis using phosphospecific antibodies revealed that both somatostat in and L-362855 induced a transient stimulation of MAP kinase which could b e desensitised by pretreatment with somatostatin, but not L-362855. The sel ective phosphoinositide (PI) 3-kinase inhibitor, LY 249002, blocked both th e somatostatin-induced increase in MAP kinase phosphorylation and extracell ular acidification. However, the MEK1 inhibitor, PD 98059, blocked only the sst, receptor-mediated stimulation of MAP kinase and not the extracellular acidification response. In summary, the human sst(4) receptor is selective ly desensitised by somatostatin and not by L-362855 and signals through two different PI 3-kinase linked pathways. (C) 1999 Academic Press.