scholarly journals Mice Lacking Homer 1 Exhibit a Skeletal Myopathy Characterized by Abnormal Transient Receptor Potential Channel Activity

2008 ◽  
Vol 28 (8) ◽  
pp. 2637-2647 ◽  
Author(s):  
Jonathan A. Stiber ◽  
Zhu-Shan Zhang ◽  
Jarrett Burch ◽  
Jerry P. Eu ◽  
Sarah Zhang ◽  
...  
Keyword(s):  
Skeletal Muscle ◽  
Transient Receptor Potential ◽  
Trp Channels ◽  
Receptor Potential ◽  
Scaffolding Protein ◽  
Channel Activity ◽  
Skeletal Muscle Function ◽  
Cross Sectional ◽  
Transient Receptor ◽  
Duchenne's Muscular Dystrophy

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.

S165F mutation of junctophilin 2 affects Ca2+ signalling in skeletal muscle

2010 ◽  
Vol 427 (1) ◽  
pp. 125-134 ◽  
Author(s):  
Jin Seok Woo ◽  
Ji-Hye Hwang ◽  
Jae-Kyun Ko ◽  
Noah Weisleder ◽  
Do Han Kim ◽  
...  
Keyword(s):  
Skeletal Muscle ◽  
Transient Receptor Potential ◽  
Receptor Potential ◽  
Dominant Negative ◽  
Skeletal Muscle Function ◽  
Primary Mouse ◽  
Pkc Protein Kinase C ◽  
Skeletal Myotubes ◽  
Transient Receptor ◽  
Canonical Type

JPs (junctophilins) contribute to the formation of junctional membrane complexes in muscle cells by physically linking the t-tubule (transverse-tubule) and SR (sarcoplasmic reticulum) membranes. In humans with HCM (hypertrophic cardiomyopathy), mutations in JP2 are linked to altered Ca2+ signalling in cardiomyocytes; however, the effects of these mutations on skeletal muscle function have not been examined. In the present study, we investigated the role of the dominant-negative JP2-S165F mutation (which is associated with human HCM) in skeletal muscle. Consistent with the hypertrophy observed in human cardiac muscle, overexpression of JP2-S165F in primary mouse skeletal myotubes led to a significant increase in myotube diameter and resting cytosolic Ca2+ concentration. Single myotube Ca2+ imaging experiments showed reductions in both the excitation–contraction coupling gain and RyR (ryanodine receptor) 1-mediated Ca2+ release from the SR. Immunoprecipitation assays revealed defects in the PKC (protein kinase C)-mediated phosphorylation of the JP2-S165F mutant protein at Ser165 and in binding of JP2-S165F to the Ca2+ channel TRPC3 (transient receptor potential cation canonical-type channel 3) on the t-tubule membrane. Therefore both the hypertrophy and altered intracellular Ca2+ signalling in the JP2-S165F-expressing skeletal myotubes can be linked to altered phosphorylation of JP2 and/or altered cross-talk among Ca2+ channels on the t-tubule and SR membranes.

scholarly journals Role of TRPC1 channel in skeletal muscle function

2010 ◽  
Vol 298 (1) ◽  
pp. C149-C162 ◽  
Author(s):  
Nadège Zanou ◽  
Georges Shapovalov ◽  
Magali Louis ◽  
Nicolas Tajeddine ◽  
Chiara Gallo ◽  
...  
Keyword(s):  
Skeletal Muscle ◽  
Muscle Function ◽  
Transient Receptor Potential ◽  
Force Production ◽  
Receptor Potential ◽  
Cross Sectional Area ◽  
Sectional Area ◽  
Skeletal Muscle Function ◽  
Cross Sectional

Skeletal muscle contraction is reputed not to depend on extracellular Ca2+. Indeed, stricto sensu , excitation-contraction coupling does not necessitate entry of Ca2+. However, we previously observed that, during sustained activity (repeated contractions), entry of Ca2+is needed to maintain force production. In the present study, we evaluated the possible involvement of the canonical transient receptor potential (TRPC)1 ion channel in this entry of Ca2+and investigated its possible role in muscle function. Patch-clamp experiments reveal the presence of a small-conductance channel (13 pS) that is completely lost in adult fibers from TRPC1−/−mice. The influx of Ca2+through TRPC1 channels represents a minor part of the entry of Ca2+into muscle fibers at rest, and the activity of the channel is not store dependent. The lack of TRPC1 does not affect intracellular Ca2+concentration ([Ca2+]i) transients reached during a single isometric contraction. However, the involvement of TRPC1-related Ca2+entry is clearly emphasized in muscle fatigue. Indeed, muscles from TRPC1−/−mice stimulated repeatedly progressively display lower [Ca2+]itransients than those observed in TRPC1+/+fibers, and they also present an accentuated progressive loss of force. Interestingly, muscles from TRPC1−/−mice display a smaller fiber cross-sectional area, generate less force per cross-sectional area, and contain less myofibrillar proteins than their controls. They do not present other signs of myopathy. In agreement with in vitro experiments, TRPC1−/−mice present an important decrease of endurance of physical activity. We conclude that TRPC1 ion channels modulate the entry of Ca2+during repeated contractions and help muscles to maintain their force during sustained repeated contractions.

scholarly journals Transient receptor potential melastatin 3 is a phosphoinositide-dependent ion channel

2015 ◽  
Vol 146 (1) ◽  
pp. 65-77 ◽  
Author(s):  
Doreen Badheka ◽  
Istvan Borbiro ◽  
Tibor Rohacs
Keyword(s):  
Ion Channel ◽  
Transient Receptor Potential ◽  
Kinase Inhibitors ◽  
Trp Channels ◽  
Receptor Potential ◽  
Channel Activity ◽  
Intact Cells ◽  
Transient Receptor Potential Melastatin ◽  
Transient Receptor ◽  
Phosphatidylinositol 4

Phosphoinositides are emerging as general regulators of the functionally diverse transient receptor potential (TRP) ion channel family. Phosphatidylinositol 4,5-bisphosphate (PI(4,5)P2) has been reported to positively regulate many TRP channels, but in several cases phosphoinositide regulation is controversial. TRP melastatin 3 (TRPM3) is a heat-activated ion channel that is also stimulated by chemical agonists, such as pregnenolone sulfate. Here, we used a wide array of approaches to determine the effects of phosphoinositides on TRPM3. We found that channel activity in excised inside-out patches decreased over time (rundown), an attribute of PI(4,5)P2-dependent ion channels. Channel activity could be restored by application of either synthetic dioctanoyl (diC8) or natural arachidonyl stearyl (AASt) PI(4,5)P2. The PI(4,5)P2 precursor phosphatidylinositol 4-phosphate (PI(4)P) was less effective at restoring channel activity. TRPM3 currents were also restored by MgATP, an effect which was inhibited by two different phosphatidylinositol 4-kinase inhibitors, or by pretreatment with a phosphatidylinositol-specific phospholipase C (PI-PLC) enzyme, indicating that MgATP acted by generating phosphoinositides. In intact cells, reduction of PI(4,5)P2 levels by chemically inducible phosphoinositide phosphatases or a voltage-sensitive 5′-phosphatase inhibited channel activity. Activation of PLC via muscarinic receptors also inhibited TRPM3 channel activity. Overall, our data indicate that TRPM3 is a phosphoinositide-dependent ion channel and that decreasing PI(4,5)P2 abundance limits its activity. As all other members of the TRPM family have also been shown to require PI(4,5)P2 for activity, our data establish PI(4,5)P2 as a general positive cofactor of this ion channel subfamily.

scholarly journals PIP2 regulation of TRPC5 channel activation and desensitization

2021 ◽  
Author(s):  
Mehek Ningoo ◽  
Leigh D. Plant ◽  
Anna Greka ◽  
Diomedes E. Logothetis
Keyword(s):  
Transient Receptor Potential ◽  
Trp Channels ◽  
Hydrolysis Product ◽  
Unmet Need ◽  
Receptor Potential ◽  
Selective Inhibition ◽  
Lanthanide Ions ◽  
Channel Activity ◽  
Transient Receptor ◽  
Trpc5 Channels

Transient receptor potential canonical type 5 (TRPC5) channels are expressed in the brain and kidney, and have been identified as promising therapeutic targets whose selective inhibition can protect against diseases driven by a leaky kidney filter. They are activated by elevated levels of extracellular Ca2+ or application of lanthanide ions but also by G protein (Gq/11) stimulation. Phosphatidylinositol bis-phosphate (PIP2) hydrolysis leads to protein kinase C- (PKC-) mediated phosphorylation of TRPC5 channels and desensitization of their activity. Even though PIP2 regulation of TRP channels is being widely studied, the roles of PIP2 in maintaining TRPC5 channel activity, the PIP2 involvement in channel stimulation by its hydrolysis product diacyl glycerol (DAG), or the desensitization of activity by DAG-stimulated PKC activity remain unclear. Here, we show that PIP2 controls both the PKC-mediated inhibition of TRPC5 currents as well as the activation by DAG and lanthanides and that it accomplishes this through control of gating rather than channel cell surface density. The mechanistic insights achieved by the present work promise to aid in the development of more selective and precise molecules to block TRPC5 channel activity and illuminate new therapeutic opportunities for targeted therapies for a group of diseases for which there is currently a great unmet need.

Intragastric administration of capsiate, a transient receptor potential channel agonist, triggers thermogenic sympathetic responses

2011 ◽  
Vol 110 (3) ◽  
pp. 789-798 ◽  
Author(s):  
Kaori Ono ◽  
Masako Tsukamoto-Yasui ◽  
Yoshiko Hara-Kimura ◽  
Naohiko Inoue ◽  
Yoshihito Nogusa ◽  
...  
Keyword(s):  
Sympathetic Nerve ◽  
Transient Receptor Potential ◽  
Trp Channels ◽  
Low Frequency ◽  
Receptor Potential ◽  
Transient Receptor Potential Channel ◽  
Intragastric Administration ◽  
Brown Adipose ◽  
Reflex Arc ◽  
Transient Receptor

The sympathetic thermoregulatory system controls the magnitude of adaptive thermogenesis in correspondence with the environmental temperature or the state of energy intake and plays a key role in determining the resultant energy storage. However, the nature of the trigger initiating this reflex arc remains to be determined. Here, using capsiate, a digestion-vulnerable capsaicin analog, we examined the involvement of specific activation of transient receptor potential (TRP) channels within the gastrointestinal tract in the thermogenic sympathetic system by measuring the efferent activity of the postganglionic sympathetic nerve innervating brown adipose tissue (BAT) in anesthetized rats. Intragastric administration of capsiate resulted in a time- and dose-dependent increase in integrated BAT sympathetic nerve activity (SNA) over 180 min, which was characterized by an emergence of sporadic high-activity phases composed of low-frequency bursts. This increase in BAT SNA was abolished by blockade of TRP channels as well as of sympathetic ganglionic transmission and was inhibited by ablation of the gastrointestinal vagus nerve. The activation of SNA was delimited to BAT and did not occur in the heart or pancreas. These results point to a neural pathway enabling the selective activation of the central network regulating the BAT SNA in response to a specific stimulation of gastrointestinal TRP channels and offer important implications for understanding the dietary-dependent regulation of energy metabolism and control of obesity.

A cell-based impedance assay for monitoring transient receptor potential (TRP) ion channel activity

2011 ◽  
Vol 26 (5) ◽  
pp. 2376-2382 ◽  
Author(s):  
Oliver Pänke ◽  
Winnie Weigel ◽  
Sabine Schmidt ◽  
Anja Steude ◽  
Andrea A. Robitzki
Keyword(s):  
Ion Channel ◽  
Transient Receptor Potential ◽  
Receptor Potential ◽  
Channel Activity ◽  
A Cell ◽  
Transient Receptor ◽  
Trp Ion Channel
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