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IP3 Receptor-Dependent Cytoplasmic Ca2+ Signals Are Tightly Controlled by Cavβ3
Anouar Belkacemi1, Xin Hui2, Barbara Wardas1
1Institut für Experimentelle und Klinische Pharmakologie und Toxikologie der Universität des Saarlandes, 66421 Homburg, Germany.
Abstract:
Voltage-gated calcium channels (Cavs) are major Ca2+ entry pathways in excitable cells. Their β subunits facilitate membrane trafficking of the channel's ion-conducting α1 pore and modulate its gating properties. We report that one β subunit, β3, reduces Ca2+ release following stimulation of phospholipase C-coupled receptors and inositol 1,4,5-trisphosphate (IP3) formation. This effect requires the SH3-HOOK domain of Cavβ3, includes physical β3/IP3 receptor interaction, and prevails when agonist-induced IP3 formation is bypassed by photolysis of caged IP3. In agreement with β3 acting as a brake on Ca2+ release, fibroblast migration is enhanced in vitro, and in vivo, closure of skin wounds is accelerated in the absence of β3. To mediate specific physiological responses and to prevent Ca2+ toxicity, cytoplasmic Ca2+ signals must be tightly controlled. The described function of β3, unrelated to its function as a Cav subunit, adds to this tight control.
Insights
The Cavβ3 subunit acts as a brake on calcium release by interacting with IP3 receptors. Its absence accelerates wound healing, highlighting its role in calcium signal control.
Area of Science:
- Cellular Biology
- Molecular Physiology
Background:
- Voltage-gated calcium channels (Cavs) are crucial for calcium (Ca2+) entry in excitable cells.
- Cav β subunits modulate channel function and membrane trafficking.
Purpose of the Study:
- To investigate the role of Cavβ3 in regulating intracellular calcium release.
- To explore the mechanism by which Cavβ3 affects calcium signaling.
Main Methods:
- Studied the effect of Cavβ3 on calcium release stimulated by phospholipase C-coupled receptors.
- Investigated the interaction between Cavβ3 and inositol 1,4,5-trisphosphate (IP3) receptors.
- Assessed fibroblast migration and skin wound closure in the presence and absence of Cavβ3.
Main Results:
- Cavβ3 significantly reduces Ca2+ release downstream of IP3 formation.
- This function requires the SH3-HOOK domain of Cavβ3 and involves direct interaction with IP3 receptors.
- Absence of Cavβ3 enhances fibroblast migration and accelerates wound healing in vivo.
Conclusions:
- Cavβ3 plays a novel role in controlling intracellular Ca2+ release, independent of its canonical function in Cavs.
- This β subunit acts as a brake on Ca2+ signaling, contributing to cellular homeostasis and physiological processes like wound repair.
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