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Tachyphylaxis of the ECL-cell response to PACAP: receptor desensitization and/or depletion of secretory products

In English

Författare

  • Maria Lundgren
  • Rolf Håkanson
  • Per Norlén

Summary, in English

Background and purpose: Rat stomach ECL cells secrete histamine and pancreastatin in response to gastrin and pituitary adenylate cyclase-activating peptide-27 ( PACAP). This study applies microdialysis to explore how ECL cells in situ respond to PACAP and gastrin. Experimental approach: Both peptides were administered by microinfusion into the gastric submucosa. The microdialysate was analysed for histamine and pancreastatin ( ECL-cell markers) and for somatostatin ( D-cell marker). Key results: Microinfusion of PACAP ( 0.01-0.3 nmol mu l(-1)) raised microdialysate histamine and pancreastatin dose-dependently. The response was powerful but short-lived. The response to gastrin was sustained at all doses tested. It is unlikely that the transient nature of the histamine response to PACAP reflects inadequate histamine synthesis, since the pancreastatin response to PACAP was short-lived too, and both gastrin and PACAP activated ECL-cell histidine decarboxylase. Unlike gastrin, PACAP mobilized somatostatin. Co-infusion of somatostatin abolished the histamine-mobilizing effect of PACAP. However, pretreatment with the somatostatin receptor type-2 antagonist ( PRL-2903) did not prolong the histamine response to PACAP, suggesting that mobilization of somatostatin does not explain the transient nature of the response. Repeated administration of 0.1 nmol mu l(-1) of PACAP ( 1 h infusions, 1 h intervals) failed to induce a second histamine response. Pretreatment with a low dose of PACAP ( 0.03 nmol mu l(-1)) abolished the response to a subsequent near-maximal PACAP challenge ( 0.3 nmol mu l(-1)). Conclusion: The transient nature of the histamine response to PACAP reflects desensitization of the PACAP receptor and/or exhaustion of a specific storage compartment that responds to PACAP but not to gastrin.

Publiceringsår

2007

Språk

Engelska

Sidor

240-248

Publikation/Tidskrift/Serie

British Journal of Pharmacology

Volym

152

Issue

2

Dokumenttyp

Artikel i tidskrift

Förlag

Wiley

Ämne

  • Pharmacology and Toxicology

Nyckelord

  • ECL cells
  • histamine
  • pancreastatin
  • histidine decarboxylase
  • microdialysis
  • gastrin
  • rat stomach
  • somatostatin
  • PACAP

Status

Published

Forskningsgrupp

  • Drug Target Discovery

ISBN/ISSN/Övrigt

  • ISSN: 1476-5381