Lester L B, Langeberg L K, Scott J D
Howard Hughes Medical Institute, Vollum Institute, 3181 S.W. Sam Jackson Park Road, Portland, OR 97201-3098, USA.
Proc Natl Acad Sci U S A. 1997 Dec 23;94(26):14942-7. doi: 10.1073/pnas.94.26.14942.
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.
胰岛素分泌受损是非胰岛素依赖型糖尿病(NIDDM)的一个特征。NIDDM的一种可能治疗药物是促胰岛素激素胰高血糖素样肽1(GLP-1)。GLP-1通过多种机制刺激胰岛素分泌,包括激活蛋白激酶A(PKA)。我们现在证明,通过与A激酶锚定蛋白(AKAP)结合实现的PKA亚细胞靶向作用促进了GLP-1介导的胰岛素分泌。引入锚定抑制肽或表达可溶性AKAP片段破坏PKA锚定,会阻断原代胰岛中的GLP-1作用以及克隆β细胞(RINm5F)中cAMP反应性胰岛素分泌。PKA的移位也阻止了cAMP介导的细胞内钙升高,这表明局部PKA磷酸化事件增强了钙通量。