Dynamic regulation of endothelial NOS mediated by competitive interaction with α-actinin-4 and calmodulin Yukio Hiroi * ,1 , Zhongmin Guo * ,1 , Yuxin Li * , Alan H. Beggs † and James K. Liao * ,2 * Vascular Medicine Research, Brigham & Women’s Hospital, and † Program in Genomics and Division of Genetics, Children’s Hospital Boston, Harvard Medical School, Boston, Massachusetts, USA 2 Correspondence: Vascular Medicine Research, Brigham & Women’s Hospital, 65 Landsdowne Street, Room 275, Boston, MA 02139, USA. E-mail: jliao@rics.bwh.harvard.edu Alpha-actinins are critical components of the actin cytoskeleton. Here we show that α-actinins serve another important biological function by binding to and competitively inhibiting calcium-dependent activation of endothelial NOS (eNOS). α-actinin-2 was found to associate with eNOS in a yeast two-hybrid screen. In vascular endothelial cells, which only express α-actinin-1 and -4, α-actinin-4 interacted and colocalized with eNOS. Addition of α-actinin-4 directly inhibited eNOS recombinant protein, and overexpression of α-actinin-4 inhibited eNOS activity in eNOS-transfected COS-7 cells and bovine aortic endothelial cells (BAECs). In contrast, knockdown of α-actinin-4 by siRNA increased eNOS activity in BAECs. The α-actinin-4-binding site on eNOS was mapped to a central region comprising the calmodulin-binding domain, and the eNOS-binding site on α-actinin-4 was mapped to the fourth spectrin-like rod domain, R4. Treatment of endothelial cells with a calcium ionophore, A23187, decreased α-actinin-4-eNOS interaction, leading to translocation of α-actinin-4 from plasma membrane to cytoplasm. Indeed, addition of calmodulin displaced α-actinin-4 binding to eNOS and increased eNOS activity. These findings indicate that eNOS activity in vascular endothelial cells is tonically and dynamically regulated by competitive interaction with α-actinin-4 and calmodulin.—Hiroi, Y., Guo, Z., Li, Y., Beggs, A. H., Liao, J. K. Dynamic regulation of endothelial NOS mediated by competitive interaction with α-actinin-4 and calmodulin. Key Words: endothelium • nitric oxide • ionophore
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Dynamic regulation of endothelial NOS mediated by competitive interaction with α-actinin-4 and calmodulin
Hiroi, Yukio; Guo, Zhongmin; Li, Yuxin; Beggs, Alan H.; Liao, James K.
Follow The FASEB Journal
, Volume 22 (5): 1450
Fed of American Socs for Experimental Biology – May 1, 2008
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