Mice lacking Homer 1 exhibit a skeletal myopathy characterized by abnormal transient receptor potential channel activity.
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.
Stiber
Jonathan A
JA
Department of Medicine, Duke University Medical Center, 4321 Medical Park Drive, Suite 200, Durham, NC 27704, USA.
Zhang
Zhu-Shan
ZS
Burch
Jarrett
J
Eu
Jerry P
JP
Zhang
Sarah
S
Truskey
George A
GA
Seth
Malini
M
Yamaguchi
Naohiro
N
Meissner
Gerhard
G
Shah
Ripal
R
Worley
Paul F
PF
Williams
R Sanders
RS
Rosenberg
Paul B
PB
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*
D002352:Carrier Proteins; D000072233:Homer Scaffolding Proteins; D050052:TRPC Cation Channels