Kalirin/Trio Rho GDP/GTP exchange factors regulate proinsulin and insulin secretion

Quinn Dufurrena, Nils Bäck, Richard Mains, Louis Hodgson, Herbert Tanowitz, Prashant Mandela, Betty Eipper, Regina Kuliawat

Research output: Contribution to journalArticle

1 Scopus citations

Abstract

Key features for progression to pancreatic β-cell failure and disease are loss of glucose responsiveness and an increased ratio of secreted proinsulin to insulin. Proinsulin and insulin are stored in secretory granules (SGs) and the fine-tuning of hormone output requires signal-mediated recruitment of select SG populations according to intracellular location and age. The GTPase Rac1 coordinates multiple signaling pathways that specify SG release, and Rac1 activity is controlled in part by GDP/GTP exchange factors (GEFs). To explore the function of two large multidomain GEFs, Kalirin and Trio in β-cells, we manipulated their Rac1-specific GEF1 domain activity by using small-molecule inhibitors and by genetically ablating Kalirin. We examined age-related SG behavior employing radiolabeling protocols. Loss of Kalirin/Trio function attenuated radioactive proinsulin release by reducing constitutive-like secretion and exocytosis of 2-h-old granules. At later chase times or at steady state, Kalirin/Trio manipulations decreased glucose-stimulated insulin output. Finally, use of a Rac1 FRET biosensor with cultured β-cell lines demonstrated that Kalirin/Trio GEF1 activity was required for normal rearrangement of Rac1 to the plasma membrane in response to glucose. Rac1 activation can be evoked by both glucose metabolism and signaling through the incretin glucagon-like peptide 1 (GLP-1) receptor. GLP-1 addition restored Rac1 localization/activity and insulin secretion in the absence of Kalirin, thereby assigning Kalirin’s participation to stimulatory glucose signaling.

Original languageEnglish (US)
Pages (from-to)47-65
Number of pages19
JournalJournal of Molecular Endocrinology
Volume62
Issue number1
DOIs
StatePublished - Jan 2019

Keywords

  • CDC42
  • Glucose signaling
  • Guanine nucleotide exchange factor (GEF)
  • Kalirin
  • Pancreatic β-cells
  • Proinsulin/insulin secretion
  • Protein sorting
  • Ras-related C3 botulinum toxin substrate 1 (Rac1)
  • Secretory granules
  • Serine/threonine-protein kinase PAK 1 (PAK1)
  • Trio

ASJC Scopus subject areas

  • Molecular Biology
  • Endocrinology

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    Dufurrena, Q., Bäck, N., Mains, R., Hodgson, L., Tanowitz, H., Mandela, P., Eipper, B., & Kuliawat, R. (2019). Kalirin/Trio Rho GDP/GTP exchange factors regulate proinsulin and insulin secretion. Journal of Molecular Endocrinology, 62(1), 47-65. https://doi.org/10.1530/JME-18-0048