Differential regulation by fatty acids of protein histidine phosphorylation in rat pancreatic islets.
Long-chain fatty acids (e.g. arachidonic acid) have been implicated in physiological control of insulin secretion. We previously reported histidine phosphorylation of at least two islet proteins (e.g., NDP kinase and the beta subunit of trimeric G-proteins), and suggested that such a signalling step may have regulatory roles in beta cell signal transduction, specifically at the level of G-protein activation. Since our earlier findings also indicated potential regulation by long-chain fatty acids of islet G-proteins, we undertook the current study to verify putative regulation, by fatty acids, of protein histidine phosphorylation of NDP kinase and Gbeta subunit in normal rat islets. The phosphoenzyme formation of NDP kinase was stimulated by various fatty acids in the following rank order: linoleic acid > arachidonic acid > oleic acid > palmitic acid = stearic acid = control. Furthermore, the catalytic activity of NDP kinase was stimulated by these fatty acids in the rank order of: oleic acid > arachidonic acid > linoleic acid > palmitic acid = stearic acid = control. Arachidonic acid methyl ester, an inactive analog of arachidonic acid, did not significantly affect either the phosphoenzyme formation or the catalytic activity of NDP kinase. Interestingly, arachidonic acid exerted dual effects on the histidine phosphorylation of beta subunit; it significantly stimulated the phosphorylation at 33 microM beyond which it was inhibitory. Together, these findings identify additional loci (e.g., NDP kinase and Gbeta subunit) at which unsaturated, but not saturated, fatty acids could exert their intracellular effects leading to exocytotic secretion of insulin.
Kowluru
Anjaneyulu
A
Department of Pharmaceutical Sciences, Wayne State University and beta Cell Biochemistry Laboratory, John D Dingell VA Medical Center, Detroit, MI 48202, USA. akowluru@med.wayne.edu
D000818:Animals; D002478:Cells, Cultured; D004305:Dose-Response Relationship, Drug; D005227:Fatty Acids / Q000494:pharmacology*; D020962:Heterotrimeric GTP-Binding Proteins / Q000378:metabolism*; D006639:Histidine / Q000378:metabolism*; D007328:Insulin / Q000096:biosynthesis; D007515:Islets of Langerhans / Q000378:metabolism*; D008297:Male; D009701:Nucleoside-Diphosphate Kinase / Q000378:metabolism*; D010766:Phosphorylation / Q000187:drug effects; D051381:Rats; D017207:Rats, Sprague-Dawley
D005227:Fatty Acids; D007328:Insulin; D006639:Histidine; D009701:Nucleoside-Diphosphate Kinase; D020962:Heterotrimeric GTP-Binding Proteins