SAD-A promotes glucose-stimulated insulin secretion through phosphorylation and inhibition of GDIα in male islet β cells

Jia Nie, Chao Sun, Zhijie Chang, Nicolas Musi, Yuguang Shi

Research output: Contribution to journalArticlepeer-review

2 Scopus citations


Rho GDP-dissociation inhibitor (GDIa) inhibits glucose-stimulated insulin secretion (GSIS) in part by locking Rho GTPases in an inactive GDP-bound form. The onset of GSIS causes phosphorylation of GDIa at Ser174, a critical inhibitory site for GDIa, leading to the release of Rho GTPases and their subsequent activation. However, the kinase regulator(s) that catalyzes the phosphorylation of GDIa in islet β cells remains elusive. We propose that SAD-A, a member of AMP-activated protein kinase-related kinases that promotes GSIS as an effector kinase for incretin signaling, interacts with and inhibits GDIa through phosphorylation of Ser174 during the onset GSIS from islet β cells. Coimmunoprecipitation and phosphorylation analyses were carried out to identify the physical interaction and phosphorylation site of GDIa by SAD-A in the context of GSIS from INS-1 β cells and primary islets. We identified GDIa directly binds to SAD-A kinase domain and phosphorylated by SAD-A on Ser174, leading to dissociation of Rho GTPases from GDIa complexes. Accordingly, overexpression of SAD-A significantly stimulated GDIa phosphorylation at Ser174 in response to GSIS, which is dramatically potentiated by glucagonlike peptide-1, an incretin hormone. Conversely, SAD-A deficiency, which is mediated by short hairpin RNA transfection in INS-1 cells, significantly attenuated endogenous GDIa phosphorylation at Ser174. Consequently, coexpression of SAD-A completely prevented the inhibitory effect of GDIa on insulin secretion in islets. In summary, glucose and incretin stimulate insulin secretion through the phosphorylation of GDIa at Ser174 by SAD-A, which leads to the activation of Rho GTPases, culminating in insulin exocytosis.

Original languageEnglish (US)
Pages (from-to)3036-3047
Number of pages12
Issue number8
StatePublished - Aug 1 2018

ASJC Scopus subject areas

  • Endocrinology


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