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(Circulation Research. 2002;91:32.)
© 2002 American Heart Association, Inc.

Molecular Medicine

Role of Sterol Regulatory Element Binding Proteins in the Regulation of G_i2 Expression in Cultured Atrial Cells

Ho-Jin Park^*, Ulrike Begley^*, Dequan Kong, Haiyan Yu, Liya Yin, F. Bradley Hillgartner, Timothy F. Osborne, Jonas B. Galper

From the Cardiovascular Division (H.-J.P., U.B., D.K., H.Y., J.B.G.), Department of Medicine, Brigham and Women’s Hospital and Harvard Medical School, Boston, Mass; the Department of Molecular Biology and Biochemistry (T.F.O.), University of California-Irvine, Irvine, Calif; and the Department of Biochemistry and Molecular Pharmacology (L.Y., F.B.H.), School of Medicine, West Virginia University, Morgantown, WV.

Correspondence to Jonas B. Galper, Dept of Medicine, Cardiovascular Division, Brigham and Women’s Hospital, 75 Francis St, Boston, MA 02115. E-Mail Galper@ calvin.bwh.harvard.edu

We have previously demonstrated that growth of embryonic chick atrial cells in medium supplemented with lipoprotein-depleted serum (LPDS) resulted in a coordinate increase in the expression of genes involved in the parasympathetic response of the heart (the M₂ muscarinic receptor; the -subunit of the heterotrimeric G protein, G_i2; and the inward rectifying K⁺ channel protein, GIRK1) and a marked increase in the negative chronotropic response of atrial cells to muscarinic stimulation. In the present study, we demonstrate that regulation of G_i2 promoter activity by LPDS is mediated by the binding of a sterol regulatory element binding protein (SREBP) to a sterol regulatory element (SRE) in the G_i2 promoter. Deletion and point mutation of this putative SRE interfered with the regulation of the G_i2 promoter by SREBP and LPDS. Furthermore gel shift assays demonstrated that point mutations in the putative G_i2 SRE markedly inhibited the binding of purified SREBP to oligonucleotides containing the G_i2 SRE sequence. The expression of a dominant-negative SREBP mutant interfered with LPDS stimulation of G_i2 promoter activity. Finally, we demonstrate that SREBP-1 is markedly more potent than SREBP-2 for the stimulation of G_i2 promoter activity, suggesting that SREBP1 may play a role in the regulation of G _i2 expression. These are the first data to demonstrate SREBP regulation of a protein not involved in lipid homeostasis and suggest a new relationship between lipid metabolism and the parasympathetic response of the heart.

Key Words: sterol regulatory element binding proteins • parasympathetic response of the heart • G proteins • G_i2

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