title: Mechanical stress-activated integrin α5β1 induces opening of connexin 43 hemichannels.
abstract: The connexin 43 (Cx43) hemichannel (HC) in the mechanosensory osteocytes is a major portal for the release of factors responsible for the anabolic effects of mechanical loading on bone formation and remodeling. However, little is known about how the Cx43 molecule responds to mechanical stimulation leading to the opening of the HC. Here, we demonstrate that integrin α5β1 interacts directly with Cx43 and that this interaction is required for mechanical stimulation-induced opening of the Cx43 HC. Direct mechanical perturbation via magnetic beads or conformational activation of integrin α5β1 leads to the opening of the Cx43 HC, and this role of the integrin is independent of its association with an extracellular fibronectin substrate. PI3K signaling is responsible for the shear stress-induced conformational activation of integrin α5β1 leading to the opening of the HC. These results identify an unconventional function of integrin that acts as a mechanical tether to induce opening of the HC and provide a mechanism connecting the effect of mechanical forces directly to anabolic function of the bone.
authors.affiliation: Department of Biochemistry, Cardiology Division, University of Texas Health Science Center, San Antonio, TX 78229, USA.
authors.forename: Nidhi
authors.initials: N
authors.lastname: Batra
authors.forename: Sirisha
authors.initials: S
authors.lastname: Burra
authors.forename: Arlene J
authors.initials: AJ
authors.lastname: Siller-Jackson
authors.forename: Sumin
authors.initials: S
authors.lastname: Gu
authors.forename: Xuechun
authors.initials: X
authors.lastname: Xia
authors.forename: Gregory F
authors.initials: GF
authors.lastname: Weber
authors.forename: Douglas
authors.initials: D
authors.lastname: DeSimone
authors.forename: Lynda F
authors.initials: LF
authors.lastname: Bonewald
authors.forename: Eileen M
authors.initials: EM
authors.lastname: Lafer
authors.forename: Eugene
authors.initials: E
authors.lastname: Sprague
authors.forename: Martin A
authors.initials: MA
authors.lastname: Schwartz
authors.forename: Jean X
authors.initials: JX
authors.lastname: Jiang
mesh_terms: D000730:Androstadienes / Q000494:pharmacology; D000818:Animals; D002460:Cell Line; D002867:Chromones / Q000494:pharmacology; D018031:Connexin 43 / Q000378:metabolism*; D016326:Extracellular Matrix Proteins / Q000378:metabolism; D005353:Fibronectins / Q000378:metabolism; D018189:Immunomagnetic Separation; D039081:Integrin alpha5beta1 / Q000037:antagonists & inhibitors / Q000502:physiology*; D051379:Mice; D009025:Morpholines / Q000494:pharmacology; D010011:Osteocytes / Q000378:metabolism*; D019869:Phosphatidylinositol 3-Kinases / Q000378:metabolism; D000081082:Phosphoinositide-3 Kinase Inhibitors; D025941:Protein Interaction Mapping; D034741:RNA, Small Interfering / Q000494:pharmacology; D013314:Stress, Mechanical; D000077191:Wortmannin
chemical_list: D000730:Androstadienes; D002867:Chromones; D018031:Connexin 43; D016326:Extracellular Matrix Proteins; D005353:Fibronectins; D039081:Integrin alpha5beta1; D009025:Morpholines; D019869:Phosphatidylinositol 3-Kinases; D000081082:Phosphoinositide-3 Kinase Inhibitors; D034741:RNA, Small Interfering; D000077191:Wortmannin; C543076:GJA1 protein, mouse; C085911:2-(4-morpholinyl)-8-phenyl-4H-1-benzopyran-4-one