IP3 Receptor-Dependent Cytoplasmic Ca2+ Signals Are Tightly Controlled by Cavβ3

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 phospho...

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Bibliographic Details
Published in:Cell reports (Cambridge) 2018-01, Vol.22 (5), p.1339-1349
Main Authors: Belkacemi, Anouar, Hui, Xin, Wardas, Barbara, Laschke, Matthias W., Wissenbach, Ulrich, Menger, Michael D., Lipp, Peter, Beck, Andreas, Flockerzi, Veit
Format: Article
Language:English
Subjects:
Ca2+ release
Ca2+ signaling
Cavβ2
Cavβ3
Cavβ3 KO
cell migration
IP3 binding
IP3 receptor
voltage-gated Ca2+ channel
wound healing
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Summary: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. [Display omitted] •Cavβ3 protein binds to the IP3 receptor and desensitizes cells to low IP3 levels•Loss of the Cavβ3 protein leads to increased IP3-dependent Ca2+ release•Enhanced Ca2+ release translates into faster migration and more collagen secretion•Mice lacking the Cacnb3 gene show more efficient skin wound healing Belkacemi et al. show that the calcium channel subunit Cavβ3 binds to the IP3R and desensitizes cells to low IP3 levels, influencing fibroblast migration and collagen secretion. Removal of the Cavβ3 protein in mice results in faster skin wound healing.
ISSN:2211-1247
2211-1247
DOI:10.1016/j.celrep.2018.01.010