Inhibition of glucose- and calcium-induced insulin secretion from betaTC3 cells by novel inhibitors of protein isoprenylation.
The majority of low molecular weight G proteins undergoes a series of post-translational modification steps, e.g., isoprenylation, at their C-terminal cysteine, which seem to be critical for the transport of the modified proteins to the membrane sites for interaction with their respective effector proteins. Using lovastatin, an inhibitor of mevalonic acid, and hence, isoprenoid biosynthesis, we demonstrated previously that protein isoprenylation is critical for physiological insulin secretion from normal rat islets. Herein, we used more selective synthetic inhibitors of protein prenylation to examine their effects on glucose- and calcium-mediated insulin secretion from betaTC3 cells. Both 3-allyl- and vinylfarnesols, which inhibit and/or modulate protein farnesyl transferases, significantly (80-95%) inhibited glucose- and KCl-stimulated insulin secretion from these cells. In a similar manner, the allyl and vinyl forms of geranylgeraniol, reagents targeted toward protein geranylation, attenuated insulin secretion elicited by glucose and KCl. Furthermore, manumycin A, a natural inhibitor of protein farnesylation, and geranylgeranyl transferase inhibitor-2147 (GGTI-2147), a peptidomimetic inhibitor of protein geranylgeranylation, also inhibited glucose- and KCl-induced insulin secretion to comparable degrees. Treatment of betaTC3 cells with either 3-vinylfarnesol or 3-vinyl geranylgeraniol resulted in accumulation of unprenylated proteins in the cytosolic fraction. These data further support our original formulation that inhibition of isoprenylation of small molecular weight G proteins might impede their interaction with their putative effectors, which may be required for physiological insulin secretion.
Amin
Rajesh
R
Department of Pharmaceutical Sciences, Wayne State University, Detroit, Michigan 48201, USA.
Chen
Hai-Qing
HQ
Tannous
Marie
M
Gibbs
Richard
R
Kowluru
Anjaneyulu
A
D019883:Alkyl and Aryl Transferases / Q000037:antagonists & inhibitors*; D000818:Animals; D002118:Calcium / Q000494:pharmacology*; D002460:Cell Line; D002470:Cell Survival / Q000187:drug effects; D004791:Enzyme Inhibitors / Q000494:pharmacology*; D019204:GTP-Binding Proteins / Q000378:metabolism; D005947:Glucose / Q000494:pharmacology*; D006160:Guanosine Triphosphate / Q000378:metabolism; D007093:Imidazoles / Q000494:pharmacology*; D007328:Insulin / Q000378:metabolism*; D000078790:Insulin Secretion; D007515:Islets of Langerhans / Q000187:drug effects / Q000378:metabolism*; D007700:Kinetics; D007930:Leucine / Q000031:analogs & derivatives / Q000494:pharmacology*; D011090:Polyenes / Q000494:pharmacology; D053284:Polyunsaturated Alkamides; D011189:Potassium Chloride / Q000494:pharmacology; D017368:Protein Prenylation / Q000187:drug effects*; D051381:Rats
D004791:Enzyme Inhibitors; C466792:GGTI 2147; D007093:Imidazoles; D007328:Insulin; D011090:Polyenes; D053284:Polyunsaturated Alkamides; D011189:Potassium Chloride; D006160:Guanosine Triphosphate; D019883:Alkyl and Aryl Transferases; C064911:p21(ras) farnesyl-protein transferase; D019204:GTP-Binding Proteins; D007930:Leucine; D005947:Glucose; C054474:manumycin; D002118:Calcium