Downstream regulatory element antagonistic modulator regulates islet prodynorphin expression.

Area of Science:

• Endocrinology
• Molecular Biology
• Neuroendocrinology

Background:

• Calcium-binding proteins are crucial regulators of pancreatic islet hormone transcription and secretion.
• Downstream regulatory element antagonistic modulator (DREAM) is a calcium-binding protein with known roles in neuronal gene expression.

Purpose of the Study:

• To investigate the neuroendocrine expression of DREAM in pancreatic islets.
• To elucidate the role of DREAM in glucose-dependent regulation of prodynorphin (PDN) expression and its impact on glucagon secretion.

Main Methods:

• Immunohistochemical localization of DREAM in pancreatic beta- and alpha-cells.
• Analysis of PDN mRNA levels in DREAM knockout islets under varying glucose conditions.
• Chromatin immunoprecipitation to assess DREAM interaction with the PDN promoter.
• Measurement of glucagon secretion in response to dynorphin A-(1-17) stimulation.

Main Results:

• DREAM is present in both the nucleus and cytoplasm of beta- and alpha-cells.
• DREAM(-/-) islets exhibit an 80% increase in PDN message under low glucose conditions (<100 nM calcium).
• DREAM inhibits PDN transcription in beta-cells by interacting with the PDN promoter's DRE in a calcium-dependent manner.
• Dynorphin A-(1-17) stimulates glucagon release from alpha-cells, and DREAM(-/-) islets show elevated glucagon secretion in low glucose.

Conclusions:

• DREAM regulates PDN transcription in pancreatic beta-cells in a calcium-dependent manner.
• Dynorphin signaling, regulated by DREAM, plays a role in controlling alpha-cell glucagon secretion.
• This study provides a molecular mechanism for opiate-stimulated glucagon secretion.