Further evidence for the regulation of acetyl-CoA carboxylase activity by a glutamate- and magnesium-activated protein phosphatase in the pancreatic beta cell: defective regulation in the diabetic GK rat islet.
We previously identified and characterized a glutamate- and magnesium-sensitive PP2A-like phosphatase (GAPP), which dephosphorylated and activated acetyl-CoA carboxylase (ACC) in the islet beta cell. Herein, we studied potential regulatory mechanisms by which GAPP is activated by glutamate and magnesium, and also quantitated the degree of activation, by glutamate- and magnesium, of ACC in normal rat islets and islets derived from the diabetic Goto-Kakizaki (GK) rat, a model for type 2 diabetes in humans. Our findings indicate that magnesium, but not glutamate, specifically activates the post-translational carboxylmethylation (CML) of the 36 kDa catalytic subunit of GAPP. Okadaic acid (OKA), which inhibits GAPP-mediated activation of ACC, also reduced the magnesium-stimulated CML of the catalytic subunit of GAPP in all the beta cell preparations studied. These data suggest that the CML step may be necessary for magnesium- and glutamate-mediated activation of ACC. We also observed a marked attenuation in magnesium- and glutamate-facilitated activation of ACC activity in islets derived from the GK rat. Together, our findings raise an interesting possibility that inhibition of GAPP-catalyzed inactivation of ACC (and subsequent reduction in the generation of long-chain fatty acids) could contribute toward the abnormalities in insulin secretion demonstrable in this animal model for type 2 diabetes.
Palanivel
Rengasamy
R
Department of Pharmaceutical Sciences, Wayne State University and beta Cell Biochemistry Laboratory, John D. Dingell VA Medical Center, Detroit, MI 48201, USA.
Veluthakal
Rajakrishnan
R
McDonald
Phillip
P
Kowluru
Anjaneyulu
A
D000103:Acetyl-CoA Carboxylase / Q000378:metabolism*; D000818:Animals; D003924:Diabetes Mellitus, Type 2 / Q000201:enzymology*; D004195:Disease Models, Animal; D004789:Enzyme Activation; D004791:Enzyme Inhibitors / Q000494:pharmacology; D018698:Glutamic Acid / Q000378:metabolism; D007515:Islets of Langerhans / Q000201:enzymology*; D008274:Magnesium / Q000378:metabolism; D008297:Male; D019319:Okadaic Acid / Q000494:pharmacology; D010749:Phosphoprotein Phosphatases / Q000037:antagonists & inhibitors / Q000378:metabolism*; D051381:Rats; D017207:Rats, Sprague-Dawley; D017208:Rats, Wistar
D004791:Enzyme Inhibitors; D019319:Okadaic Acid; D018698:Glutamic Acid; D010749:Phosphoprotein Phosphatases; D000103:Acetyl-CoA Carboxylase; D008274:Magnesium