title: Mice lacking Homer 1 exhibit a skeletal myopathy characterized by abnormal transient receptor potential channel activity.
abstract: Transient receptor potential (TRP) channels are nonselective cation channels, several of which are expressed in striated muscle. Because the scaffolding protein Homer 1 has been implicated in TRP channel regulation, we hypothesized that Homer proteins play a significant role in skeletal muscle function. Mice lacking Homer 1 exhibited a myopathy characterized by decreased muscle fiber cross-sectional area and decreased skeletal muscle force generation. Homer 1 knockout myotubes displayed increased basal current density and spontaneous cation influx. This spontaneous cation influx in Homer 1 knockout myotubes was blocked by reexpression of Homer 1b, but not Homer 1a, and by gene silencing of TRPC1. Moreover, diminished Homer 1 expression in mouse models of Duchenne's muscular dystrophy suggests that loss of Homer 1 scaffolding of TRP channels may contribute to the increased stretch-activated channel activity observed in mdx myofibers. These findings provide direct evidence that Homer 1 functions as an important scaffold for TRP channels and regulates mechanotransduction in skeletal muscle.
authors.affiliation: Department of Medicine, Duke University Medical Center, 4321 Medical Park Drive, Suite 200, Durham, NC 27704, USA.
authors.forename: Jonathan A
authors.initials: JA
authors.lastname: Stiber
authors.forename: Zhu-Shan
authors.initials: ZS
authors.lastname: Zhang
authors.forename: Jarrett
authors.initials: J
authors.lastname: Burch
authors.forename: Jerry P
authors.initials: JP
authors.lastname: Eu
authors.forename: Sarah
authors.initials: S
authors.lastname: Zhang
authors.forename: George A
authors.initials: GA
authors.lastname: Truskey
authors.forename: Malini
authors.initials: M
authors.lastname: Seth
authors.forename: Naohiro
authors.initials: N
authors.lastname: Yamaguchi
authors.forename: Gerhard
authors.initials: G
authors.lastname: Meissner
authors.forename: Ripal
authors.initials: R
authors.lastname: Shah
authors.forename: Paul F
authors.initials: PF
authors.lastname: Worley
authors.forename: R Sanders
authors.initials: RS
authors.lastname: Williams
authors.forename: Paul B
authors.initials: PB
authors.lastname: Rosenberg
mesh_terms: D000818:Animals; D020013:Calcium Signaling; D002352:Carrier Proteins / Q000235:genetics* / Q000378:metabolism*; D002478:Cells, Cultured; D004195:Disease Models, Animal; D017353:Gene Deletion; D005786:Gene Expression Regulation; D000072233:Homer Scaffolding Proteins; D051379:Mice; D018345:Mice, Knockout; D009119:Muscle Contraction; D009136:Muscular Dystrophies / Q000235:genetics / Q000473:pathology / Q000503:physiopathology*; D011485:Protein Binding; D050052:TRPC Cation Channels / Q000235:genetics / Q000378:metabolism*
chemical_list: D002352:Carrier Proteins; D000072233:Homer Scaffolding Proteins; D050052:TRPC Cation Channels