The role of cytosolic phospholipase A(2) in insulin secretion.
Cytosolic phospholipase A(2) (cPLA(2)) comprises a widely expressed family of enzymes, some members of which have the properties required of signal transduction elements in electrically excitable cells. Thus, alpha- and beta-isoforms of cPLA(2) are activated by the increases in intracellular Ca(2+) concentration ([Ca(2+)](i)) achieved in depolarized cells. Activation is associated with a redistribution of the enzyme within the cell; activation of cPLA(2) generates arachidonic acid (AA), a biologically active unsaturated fatty acid that can be further metabolized to generate a plethora of biologically active molecules. Studies using relatively nonselective pharmacological inhibitors have implicated cPLA(2) in insulin secretory responses to stimuli that elevate beta-cell [Ca(2+)](i); therefore, we have investigated the role of cPLA(2) in beta-cell function by generating beta-cell lines that under- or overexpress the alpha-isoform of cPLA(2). The functional phenotype of the modified cells was assessed by observation of cellular ultrastructure, by measuring insulin gene expression and insulin protein content, and by measuring the effects of insulin secretagogues on cPLA(2) distribution, on changes in [Ca(2+)](i), and on the rate and pattern of insulin secretion. Our results suggest that cPLA(2) is not required for the initiation of insulin secretion from beta-cells, but that it plays an important role in the maintenance of beta-cell insulin stores. Our data also demonstrate that excessive production of, or exposure to, AA is deleterious to normal beta-cell secretory function through metabolic dysfunction.
Jones
Peter M
PM
Centre for Reproduction, Endocrinology and Diabetes, GKT School of Biomedical Sciences, King's College London, London, UK. peter.jones@kcl.ac.uk
Burns
Christopher J
CJ
Belin
Véronique D
VD
Roderigo-Milne
Helen M
HM
Persaud
Shanta J
SJ
D000818:Animals; D016718:Arachidonic Acid / Q000378:metabolism; D003600:Cytosol / Q000201:enzymology*; D006801:Humans; D007328:Insulin / Q000235:genetics / Q000378:metabolism*; D000078790:Insulin Secretion; D007515:Islets of Langerhans / Q000201:enzymology / Q000378:metabolism*; D007700:Kinetics; D010741:Phospholipases A / Q000172:deficiency / Q000235:genetics / Q000378:metabolism*; D011384:Proinsulin / Q000235:genetics; D011498:Protein Precursors / Q000235:genetics; D021381:Protein Transport; D012333:RNA, Messenger / Q000235:genetics; D051381:Rats
D007328:Insulin; D011498:Protein Precursors; D012333:RNA, Messenger; D016718:Arachidonic Acid; C013737:preproinsulin; D011384:Proinsulin; D010741:Phospholipases A