Discovery of pituitary adenylate cyclase-activating polypeptide-regulated genes through microarray analyses in cell culture and in vivo

Lee E. Eiden, Babru Samal, Matthew J. Gerdin, Tomris Mustafa, David Vaudry, Nikolas Stroth

Research output: Chapter in Book/Report/Conference proceedingConference PaperResearchpeer-review

16 Citations (Scopus)

Abstract

Pituitary adenylate cyclase-activating polypeptide (PACAP) is an evolutionarily well conserved neuropeptide with multiple functions in the nervous, endocrine, and immune systems. PACAP provides neuroprotection from ischemia and toxin exposure, is anti-inflammatory in gastric inflammatory disease and sepsis, controls proliferative signaling pathways involved in neural cell transformation, and modulates glucohomeostasis. PACAP-based, disease-targeted therapeutics might thus be both effective and benign, enhancing homeostatic responses to behavioral, metabolic, oncogenic, and inflammatory stressors. PACAP signal transduction employs synergistic regulation of calcium and cyclic adenosine monophosphate (cAMP), and noncanonical activation of both calcium- and cAMP-dependent processes. Pharmacological activation of PACAP signaling should consequently have highly specific effects even in vivo. Here, a combined cellular biochemical, pharmacologic, transcriptomic, and bioinformatic approach to understanding PACAP signal transduction by identifying PACAP target genes with oligonucleotide- and cDNA-based microarray is described. Calcium- and cAMP-dependent PACAP signaling pathways for regulation of genes encoding proteins required for neuritogenesis, changes in cell morphology, and cell survival have been traced in PC12 cells. Pharmacological experiments have linked gene expression to cell physiological responses in this system, in which gene silencing can also be employed to confirm the functional significance of induction of specific transcripts. Differential transcriptional responses to metabolic, ischemic, and other stressors in wild type compared to PACAP-deficient mice establish in principle which PACAP-responsive transcripts in culture are PACAP-dependent in vivo. Bioinformatic approaches aid in creating a pipeline for identifying neuropeptide-regulated genes, validating their cellular functions, and defining their expression in the context of neuropeptide signaling physiology, required for discovery of new targets for drug action.

Original languageEnglish
Title of host publicationNeural Signaling Opportunities for Novel Diagnostic Approaches and Therapies
PublisherBlackwell Publishing Inc.
Pages6-20
Number of pages15
ISBN (Print)9781573317047
DOIs
Publication statusPublished - 1 Jan 2008
Externally publishedYes

Publication series

NameAnnals of the New York Academy of Sciences
Volume1144
ISSN (Print)0077-8923
ISSN (Electronic)1749-6632

Keywords

  • Bioinformatics
  • Gene discovery
  • Microarray
  • Neuropeptide
  • Neuroprotection
  • PACAP
  • PC12
  • Pituitary adenylate cyclase-activating polypeptide
  • Signal transduction
  • Stress response

Cite this

Eiden, L. E., Samal, B., Gerdin, M. J., Mustafa, T., Vaudry, D., & Stroth, N. (2008). Discovery of pituitary adenylate cyclase-activating polypeptide-regulated genes through microarray analyses in cell culture and in vivo. In Neural Signaling Opportunities for Novel Diagnostic Approaches and Therapies (pp. 6-20). (Annals of the New York Academy of Sciences; Vol. 1144). Blackwell Publishing Inc.. https://doi.org/10.1196/annals.1418.019