title: PACAP and gastrin regulate the histidine decarboxylase promoter via distinct mechanisms.
abstract: The enterochromaffin-like (ECL) cell controls gastric acid secretion via histamine, generated by l-histidine decarboxylase (HDC). HDC expression is regulated by gastrin. However, gastrin is not alone in controlling ECL cell function. For example, the neural peptide pituitary adenylate cyclase-activating polypeptide (PACAP) also increases ECL cell proliferation. To investigate a potential role of PACAP in regulating HDC expression, we generated a series of HDC promoter-luciferase reporter constructs and transiently transfected them into PC12 cells (stably expressing the gastrin-CCK-2 receptor). We found that PACAP regulates HDC promoter activity. This is temporally biphasic, involving both adenyl cyclase and phospholipase C-dependent pathways. Deletional analysis, block mutation, and EMSA demonstrated a PACAP-response element at -177 to -170, wholly necessary for the effects of PACAP and discrete from known gastrin-responsive elements. Discrete neural and endocrine pathways regulate ECL cells through different patterns of postreceptor signaling and promoter activation, which may be appropriate to their functions in vivo.
authors.affiliation: Gastrointestinal Sciences, University of Manchester, Hope Hospital, Salford M6 H8D United Kingdom.
authors.forename: John T
authors.initials: JT
authors.lastname: McLaughlin
authors.forename: Wandong
authors.initials: W
authors.lastname: Ai
authors.forename: Natalie F
authors.initials: NF
authors.lastname: Sinclair
authors.forename: Rocchina
authors.initials: R
authors.lastname: Colucci
authors.forename: Raktima
authors.initials: R
authors.lastname: Raychowdhury
authors.forename: Theodore J
authors.initials: TJ
authors.lastname: Koh
authors.forename: Timothy C
authors.initials: TC
authors.lastname: Wang
mesh_terms: D000262:Adenylyl Cyclases / Q000378:metabolism; D000818:Animals; D005576:Colforsin / Q000494:pharmacology; D024202:Electrophoretic Mobility Shift Assay; D005755:Gastrins / Q000494:pharmacology*; D015971:Gene Expression Regulation, Enzymologic / Q000187:drug effects*; D006640:Histidine Decarboxylase / Q000235:genetics*; D006801:Humans; D008156:Luciferases / Q000235:genetics; D009479:Neuropeptides / Q000494:pharmacology*; D016716:PC12 Cells; D051219:Pituitary Adenylate Cyclase-Activating Polypeptide; D011401:Promoter Regions, Genetic / Q000187:drug effects*; D051381:Rats; D043887:Receptor, Cholecystokinin B / Q000187:drug effects / Q000235:genetics; D011949:Receptors, Cholecystokinin / Q000187:drug effects / Q000235:genetics; D015398:Signal Transduction / Q000187:drug effects / Q000235:genetics; D014162:Transfection
chemical_list: C495401:ADCYAP1 protein, human; C495403:Adcyap1 protein, rat; D005755:Gastrins; D009479:Neuropeptides; D051219:Pituitary Adenylate Cyclase-Activating Polypeptide; D043887:Receptor, Cholecystokinin B; D011949:Receptors, Cholecystokinin; D005576:Colforsin; D008156:Luciferases; D006640:Histidine Decarboxylase; D000262:Adenylyl Cyclases