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Dominant-Negative -Subunit of Farnesyl- and Geranyltransferase Inhibits Glucose-Stimulated, but Not KCl-Stimulated, Insulin Secretion in INS 832/13 Cells

¹ Department of Pharmaceutical Sciences, Eugene Applebaum College of Pharmacy and Health Sciences, Wayne State University, Detroit, Michigan and Beta Cell Biochemistry Research Laboratory, John D. Dingell Veterans Affairs Medical Center, Detroit, Michigan
² Research Service, Denver Veterans Affairs Medical Center, Denver, Colorado and Department of Medicine, University of Colorado Health Sciences Center, Denver, Colorado

Address correspondence and reprint requests to Anjan Kowluru, PhD, 3601, Eugene Applebaum College of Pharmacy and Health Sciences, Wayne State University, 259 Mack Ave., Detroit, MI 48201. E-mail: akowluru{at}med.wayne.edu

Abbreviations: ELISA, enzyme-linked immunosorbent assay; FTase, farnesyltransferase; GDI, GDP dissociation inhibitor; GGTase, geranylgeranyltransferase; GGTI, GGTase inhibitor; GSIS, glucose-stimulated insulin secretion; PPTase, protein prenyltransferase

The majority of small G-proteins undergo posttranslational modifications (e.g., isoprenylation) at their C-terminal cysteine residues. Such modifications increase their hydrophobicity, culminating in translocation of the modified proteins to their relevant membranous sites for interaction with their respective effectors. Previously, we reported glucose-dependent activation and membrane association of Rac1 in INS 832/13 cells. We also demonstrated modulatory roles for Rac1/GDP dissociation inhibitor in glucose-stimulated insulin secretion (GSIS) in INS 832/13 cells, further affirming roles for Rac1 in GSIS. Herein, we demonstrate that geranylgeranyltransferase inhibitor-2147 (GGTI-2147), an inhibitor of protein prenylation, markedly increased cytosolic accumulation of Rac1 and elicited significant inhibition of GSIS from INS 832/13 cells. In the current study, we also examined the localization of protein prenyltransferases (PPTases) and regulation of GSIS by PPTases in INS 832/13 cells. Western blot analyses indicated that the regulatory -subunit and the structural ß-subunit of PPTase holoenzyme are predominantly cytosolic in their distribution. Overexpression of an inactive mutant of the regulatory -subunit of PPTase markedly attenuated glucose- but not KCl-induced insulin secretion from INS 832/13 cells. Together, our findings provide the first evidence for the regulation of GSIS by PPTase in INS 832/13 cells. Furthermore, they support our original hypothesis that prenylation of specific G-proteins may be necessary for GSIS.

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