Mammalian bombesin receptors are coupled to multiple signal transduction pathways in pancreatic acini.
We investigated the structural requirements for bombesin (BB)-like peptides to stimulate amylase secretion in rat pancreatic acini and examined the responsible intracellular signal transduction pathways. The tetradecapeptide BB-(1-14) was a full agonist, whereas the heptapeptide BB-(8-14) did not evoke amylase secretion. The mammalian BB analog neuromedin C decapeptide [NMC-(5-14)] was as potent as BB-(1-14) in stimulating amylase secretion, suggesting that Gly5-Asn6-His7 (or Gln7) of the COOH-terminal decapeptide are essential amino acids for full biological activity. BB and NMC equipotently stimulated D-myo-inositol 1,4,5-trisphosphate production, which was inhibited by the phospholipase C (PLC) inhibitor U-73122. BB and NMC also stimulated protein tyrosine kinase (PTK) activities. The half-maximal effective concentration (EC50) for NMC-activated PTK was 2 log units less than the EC50 for BB-activated PTK. NMC was 10-34 times more potent than BB in increasing leukotriene C4 (an index of arachidonic acid production). The production of leukotriene C4 was inhibited by the phospholipase A2 (PLA2) inhibitor ONO-RS-082. NMC is structurally homologous to BB-(5-14) except that Gln7 in BB is replaced by His7 in NMC. Therefore, substitution of Gln7 for His7 may alter the signal transduction systems to include the PTK and PLA2 pathways. U-73122 inhibited Ca2+ spiking and amylase secretion induced by NMC and BB. However, the PTK inhibitor genistein and the PLA2 inhibitor ONO-RS-082 inhibited secretion induced by NMC but not that induced by BB. In contrast to nonmammalian BB receptors, which primarily use the PLC pathway, the rat BB receptor is linked to three different signal transduction systems: PLC, PTK, and PLA2 pathways.
Nishino
H
H
Department of Internal Medicine, University of Michigan, Ann Arbor 48109, USA.
Tsunoda
Y
Y
Owyang
C
C
D000595:Amino Acid Sequence; D062365:Aminobenzoates / Q000494:pharmacology; D000681:Amylases / Q000378:metabolism*; D000818:Animals; D001839:Bombesin / Q000031:analogs & derivatives* / Q000737:chemistry / Q000378:metabolism; D002723:Chlorobenzoates; D002934:Cinnamates / Q000494:pharmacology; D004791:Enzyme Inhibitors / Q000494:pharmacology; D004963:Estrenes / Q000494:pharmacology; D006801:Humans; D006893:Hydroxyeicosatetraenoic Acids / Q000378:metabolism; D015544:Inositol 1,4,5-Trisphosphate / Q000378:metabolism; D008969:Molecular Sequence Data; D015287:Neurokinin B / Q000031:analogs & derivatives / Q000737:chemistry / Q000378:metabolism; D010179:Pancreas / Q000187:drug effects / Q000201:enzymology*; D010446:Peptide Fragments / Q000737:chemistry / Q000378:metabolism; D010726:Phosphodiesterase Inhibitors / Q000494:pharmacology; D010741:Phospholipases A / Q000037:antagonists & inhibitors; D054467:Phospholipases A2; D011505:Protein-Tyrosine Kinases / Q000378:metabolism; D011760:Pyrrolidinones / Q000494:pharmacology; D011863:Radioimmunoassay; D051381:Rats; D018004:Receptors, Bombesin / Q000378:metabolism*; D015398:Signal Transduction / Q000187:drug effects; D013329:Structure-Activity Relationship; D013552:Swine; D010738:Type C Phospholipases / Q000037:antagonists & inhibitors; D062367:ortho-Aminobenzoates
D062365:Aminobenzoates; D002723:Chlorobenzoates; D002934:Cinnamates; D004791:Enzyme Inhibitors; D004963:Estrenes; D006893:Hydroxyeicosatetraenoic Acids; D010446:Peptide Fragments; D010726:Phosphodiesterase Inhibitors; D011760:Pyrrolidinones; D018004:Receptors, Bombesin; D062367:ortho-Aminobenzoates; C060229:1-(6-((3-methoxyestra-1,3,5(10)-trien-17-yl)amino)hexyl)-1H-pyrrole-2,5-dione; C025984:15-hydroxy-5,8,11,13-eicosatetraenoic acid; C040794:neuromedin C; D015544:Inositol 1,4,5-Trisphosphate; D015287:Neurokinin B; C038393:neuromedin B; C060048:2-(4-amylcinnamoyl)amino-4-chlorobenzoic acid; D011505:Protein-Tyrosine Kinases; D010741:Phospholipases A; D054467:Phospholipases A2; D010738:Type C Phospholipases; D000681:Amylases; D001839:Bombesin