title: Global cytoskeletal control of mechanotransduction in kidney epithelial cells.
abstract: Studies of mechanotransduction mediated by stress-sensitive ion channels generally focus on the site of force application to the cell. Here we show that global, cell-wide changes in cytoskeletal structure and mechanics can regulate mechanotransduction previously shown to be triggered by activation of the mechanosensitive calcium channel, polycystin-2, in the apical primary cilium of renal epithelial cells [S.M. Nauli, F.J. Alenghat, Y. Luo, E. Williams, P. Vassilev, X. Li, A.E. Elia, W. Lu, E.M. Brown, S.J. Quinn, D.E. Ingber, J. Zhou, Polycystins 1 and 2 mediate mechanosensation in the primary cilium of kidney cells. Nat. Genet. 33 (2003) 129-37]. Disrupting cytoplasmic microfilaments or microtubules in these cells eliminated fluid shear stress-induced increase of intracellular calcium. Altering the cytoskeletal force balance by inhibiting actomyosin-based tension generation (using 2,3-butanedione monoxime), interfering with microtubule polymerization (using nocodazole, cochicine, or taxol), or disrupting basal integrin-dependent extracellular matrix adhesions (using soluble GRGDSP peptide or anti-beta1 integrin antibody), also inhibited the calcium spike in response to fluid stress. These data indicate that although fluid stress-induced displacement of the primary cilium may be transduced into a calcium spike through activation of polycystin-2 and associated calcium-induced calcium release from intracellular stores, this mechanotransduction response is governed by global mechanical cues, including isometric tension (prestress) within the entire cytoskeleton and intact adhesions to extracellular matrix.
authors.affiliation: Vascular Biology Program, Departments of Pathology and Surgery, Children's Hospital, Harvard Medical School, Boston, MA 02115, USA.
authors.forename: Francis J
authors.initials: FJ
authors.lastname: Alenghat
authors.forename: Surya M
authors.initials: SM
authors.lastname: Nauli
authors.forename: Robert
authors.initials: R
authors.lastname: Kolb
authors.forename: Jing
authors.initials: J
authors.lastname: Zhou
authors.forename: Donald E
authors.initials: DE
authors.lastname: Ingber
mesh_terms: D008841:Actin Cytoskeleton / Q000378:metabolism*; D000199:Actins / Q000502:physiology*; D000818:Animals; D000970:Antineoplastic Agents / Q000494:pharmacology; D002118:Calcium / Q000378:metabolism*; D002135:Calcium-Binding Proteins / Q000378:metabolism; D002448:Cell Adhesion; D002478:Cells, Cultured; D002923:Cilia / Q000378:metabolism; D003593:Cytoplasm / Q000378:metabolism; D003599:Cytoskeleton; D004847:Epithelial Cells / Q000187:drug effects / Q000378:metabolism*; D005109:Extracellular Matrix / Q000378:metabolism; D007668:Kidney / Q000187:drug effects / Q000378:metabolism*; D040542:Mechanotransduction, Cellular / Q000502:physiology*; D008565:Membrane Proteins / Q000378:metabolism; D051379:Mice; D008870:Microtubules / Q000378:metabolism*; D015739:Nocodazole / Q000494:pharmacology; D050396:TRPP Cation Channels
chemical_list: D000199:Actins; D000970:Antineoplastic Agents; D002118:Calcium; D002135:Calcium-Binding Proteins; D008565:Membrane Proteins; D015739:Nocodazole; D050396:TRPP Cation Channels