Anchoring of Protein Kinase A Facilitates Hormone-Mediated Insulin Secretion

Impaired insulin secretion is a characteristic of non-insulin-dependent diabetes mellitus (NIDDM). One possible therapeutic agent for NIDDM is the insulinotropic hormone glucagon-like peptide 1 (GLP-1). GLP-1 stimulates insulin secretion through several mechanisms including activation of protein kin...

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Bibliographic Details
Published in:Proceedings of the National Academy of Sciences - PNAS 1997-12, Vol.94 (26), p.14942-14947
Main Authors: Lester, L B, Langeberg, L K, Scott, J D
Format: Article
Language:English
Subjects:
Agonists
Animals
Beta cells
Biological Sciences
Calcium
Calcium - metabolism
Cell lines
Cells, Cultured
Cellular biology
Cyclic AMP-Dependent Protein Kinases - metabolism
Diabetes Mellitus, Type 2 - metabolism
Endocrine system
Genes
Glucagon - pharmacology
Glucagon-Like Peptide 1
Hormones
Insulin
Insulin - metabolism
Insulin Secretion
Islet cells
Islets of Langerhans
Pancreas - metabolism
Peptide Fragments - pharmacology
Phosphorylation
Protein Precursors - pharmacology
Proteins
Radioimmunoassay
Rats
Rodents
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Summary:Impaired insulin secretion is a characteristic of non-insulin-dependent diabetes mellitus (NIDDM). One possible therapeutic agent for NIDDM is the insulinotropic hormone glucagon-like peptide 1 (GLP-1). GLP-1 stimulates insulin secretion through several mechanisms including activation of protein kinase A (PKA). We now demonstrate that the subcellular targeting of PKA through association with A-kinase-anchoring proteins (AKAPs) facilitates GLP-1-mediated insulin secretion. Disruption of PKA anchoring by the introduction of anchoring inhibitor peptides or expression of soluble AKAP fragments blocks GLP-1 action in primary islets and cAMP-responsive insulin secretion in clonal beta cells (RINm5F). Displacement of PKA also prevented cAMP-mediated elevation of intracellular calcium suggesting that localized PKA phosphorylation events augment calcium flux.
ISSN:0027-8424
1091-6490
DOI:10.1073/pnas.94.26.14942