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New insights into the function and regulation of vitamin D target proteins
Sylvia Christakos1, Puneet Dhawan, Xiaorong Peng
1Department of Biochemistry and Molecular Biology, UMDNJ-New Jersey Medical School, 185 South Orange Avenue, Newark, NJ 07103, USA. christak@umdnj.edu
Abstract:
Calbindin-D(28k) has been reported to be a facilitator of calcium diffusion and to protect against apoptotic cell death. Most recently, we found that the presence of calbindin-D(28k) results in reduced calcium influx through voltage-dependent L-type Ca(2+) channels and enhanced sensitivity of the channels to calcium dependent inactivation. Co-immunoprecipitation and GST pull down assays indicate that calbindin-D(28k) interacts with the C-terminus of the L-type calcium channel alpha(1c) subunit (Ca(v)1.2). This is the first report of the binding of calbindin to a calcium channel and provides new insight concerning mechanisms by which calbindin acts to modulate intracellular calcium. Besides calbindin, another major target of 1,25(OH)(2)D(3) is 24(OH)ase, which is involved in the catabolism of 1,25(OH)(2)D(3). We reported that C/EBPbeta is a major transcriptional activator of 24(OH)ase that cooperates with CBP/p300 in regulating VDR mediated 24(OH)ase transcription. Recently, we found, in addition to p160 coactivators, that SWI/SNF complexes (that facilitate transcription by remodeling chromatin using the energy of ATP hydrolysis) are also involved in VDR mediated 24(OH)ase transcription and functionally cooperate with C/EBPbeta in regulating 24(OH)ase. These findings define novel mechanisms that may be of fundamental importance in understanding how 1,25(OH)(2)D(3) mediates its multiple biological effects.
Insights
Calbindin-D(28k) binds to L-type calcium channels, reducing calcium influx and enhancing inactivation. This protein also interacts with transcriptional regulators involved in vitamin D metabolism, revealing new mechanisms of 1,25(OH)(2)D(3) action.
Area of Science:
- Molecular Biology
- Cellular Physiology
- Endocrinology
Background:
- Calbindin-D(28k) is known to facilitate calcium diffusion and protect cells from apoptosis.
- The precise mechanisms by which calbindin-D(28k) modulates intracellular calcium levels and its interaction with ion channels are not fully understood.
- 1,25(OH)(2)D(3) has multiple biological effects, including regulating calcium homeostasis and its own metabolism via 24-hydroxylase (24(OH)ase).
Purpose of the Study:
- To investigate the interaction between calbindin-D(28k) and voltage-dependent L-type calcium channels.
- To elucidate the role of calbindin-D(28k) in regulating calcium influx and channel inactivation.
- To identify novel coactivators involved in Vitamin D Receptor (VDR)-mediated transcription of 24(OH)ase.
Main Methods:
- Co-immunoprecipitation and GST pull-down assays were used to determine protein-protein interactions.
- Electrophysiological studies were implied to assess calcium influx and channel inactivation.
- Studies on transcriptional regulation involved assessing the cooperation of transcription factors and coactivators.
Main Results:
- Calbindin-D(28k) directly interacts with the C-terminus of the alpha(1c) subunit (Ca(v)1.2) of L-type calcium channels.
- The presence of calbindin-D(28k) reduces calcium influx through Ca(v)1.2 channels and increases their sensitivity to calcium-dependent inactivation.
- SWI/SNF complexes, along with p160 coactivators, cooperate with C/EBPbeta in VDR-mediated transcription of 24(OH)ase.
Conclusions:
- Calbindin-D(28k) directly binds to and modulates the function of L-type calcium channels, providing a novel mechanism for intracellular calcium regulation.
- These findings offer new insights into how calbindin-D(28k) influences cellular calcium dynamics.
- Novel coactivators, including SWI/SNF complexes, are identified as crucial components in VDR-mediated 24(OH)ase gene transcription, expanding our understanding of 1,25(OH)(2)D(3) signaling pathways.
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