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PLoS One. 2015 Apr 22;10(4):e0124274. doi: 10.1371/journal.pone.0124274. eCollection 2015.

Forskolin Regulates L-Type Calcium Channel through Interaction between Actinin 4 and β3 Subunit in Osteoblasts.

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Department of Pharmacology, School of Pharmacy, Fudan University, 826 Zhangheng Road, Pudong New District, Shanghai, 201203, China.
Department of Pharmacy, Jing'an District Center Hospital of Shanghai (Huashan Hospital, Fudan University, Jing'an Branch), 259 Xikang Road, Shanghai, 200040, China.
Department of Nephrology, Putuo Hospital, Shanghai University of Traditional Chinese Medicine,164 Lanxi Road, Shanghai, 200062, PR China.
Renal Division, Department of Medicine, Emory University School of Medicine, Atlanta, GA, 30322, United States of America; Renal Section, Atlanta Veteran Administration Medical Center, Decatur, GA, 30033, United States of America.


Voltage-dependent L-type calcium channels that permit cellular calcium influx are essential in calcium-mediated modulation of cellular signaling. Although the regulation of voltage-dependent L-type calcium channels is linked to many factors including cAMP-dependent protein kinase A (PKA) activity and actin cytoskeleton, little is known about the detailed mechanisms underlying the regulation in osteoblasts. Our present study investigated the modulation of L-type calcium channel activities through the effects of forskolin on actin reorganization and on its functional interaction with actin binding protein actinin 4. The results showed that forskolin did not significantly affect the trafficking of pore forming α1c subunit and its interaction with actin binding protein actinin 4, whereas it significantly increased the expression of β3 subunit and its interaction with actinin 4 in osteoblast cells as assessed by co-immunoprecipitation, pull-down assay, and immunostaining. Further mapping showed that the ABD and EF domains of actinin 4 were interaction sites. This interaction is independent of PKA phosphorylation. Knockdown of actinin 4 significantly decreased the activities of L-type calcium channels. Our study revealed a new aspect of the mechanisms by which the forskolin activation of adenylyl cyclase - cAMP cascade regulates the L-type calcium channel in osteoblast cells, besides the PKA mediated phosphorylation of the channel subunits. These data provide insight into the important role of interconnection among adenylyl cyclase, cAMP, PKA, the actin cytoskeleton, and the channel proteins in the regulation of voltage-dependent L-type calcium channels in osteoblast cells.

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