Submitted on May 9, 2002
Accepted on June 3, 2003
PACAP AND GASTRIN REGULATE THE HISTIDINE DECARBOXYLASE PROMOTER VIA DISTINCT MECHANISMS
John T McLaughlin1, Wandong Ai2, Natalie F. Sinclair2, Rocchina Colucci3, Raktima Raychowdhury3, Theodore J Koh2, and Timothy C Wang2*
1 Gastrointestinal Sciences, University of Manchester, Hope Hospital, Manchester, United Kingdom
2 Division of Digestive Diseases and Nutrition, UMass Memorial Medical, Worcester, MA, USA
3 Gastrointestinal Unit, Massachusetts General Hospital, Boston, MA, USA
* To whom correspondence should be addressed. E-mail: Timothy.Wang{at}UMassmed.edu.
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 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-CCK2 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 electrophoretic mobility shift assays demonstrated a PACAP-response element (PRE) 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 post receptor signaling and promoter activation, which may be appropriate to their functions in vivo.
