Interaction of vitamin D with membrane-based signaling pathways
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María Jesús Larriba1, José Manuel González-Sancho1, Félix Bonilla2
1Instituto de Investigaciones Biomédicas "Alberto Sols," Consejo Superior de Investigaciones Científicas, Universidad Autónoma de Madrid Madrid, Spain.
Abstract:
Many studies in different biological systems have revealed that 1α,25-dihydroxyvitamin D3 (1α,25(OH)2D3) modulates signaling pathways triggered at the plasma membrane by agents such as Wnt, transforming growth factor (TGF)-β, epidermal growth factor (EGF), and others. In addition, 1α,25(OH)2D3 may affect gene expression by paracrine mechanisms that involve the regulation of cytokine or growth factor secretion by neighboring cells. Moreover, post-transcriptional and post-translational effects of 1α,25(OH)2D3 add to or overlap with its classical modulation of gene transcription rate. Together, these findings show that vitamin D receptor (VDR) cannot be considered only as a nuclear-acting, ligand-modulated transcription factor that binds to and controls the transcription of target genes. Instead, available data support the view that much of the complex biological activity of 1α,25(OH)2D3 resides in its capacity to interact with membrane-based signaling pathways and to modulate the expression and secretion of paracrine factors. Therefore, we propose that future research in the vitamin D field should focus on the interplay between 1α,25(OH)2D3 and agents that act at the plasma membrane, and on the analysis of intercellular communication. Global analyses such as RNA-Seq, transcriptomic arrays, and genome-wide ChIP are expected to dissect the interactions at the gene and molecular levels.
Insights
1α,25-dihydroxyvitamin D3 (1α,25(OH)2D3) interacts with cell membrane pathways and influences intercellular communication, expanding its known role beyond nuclear gene transcription. Future vitamin D research should explore these membrane interactions and paracrine signaling mechanisms.
Area of Science:
- Endocrinology
- Molecular Biology
- Cell Signaling
Background:
- 1α,25-dihydroxyvitamin D3 (1α,25(OH)2D3) is known to modulate various signaling pathways.
- Its effects extend beyond classical nuclear gene transcription modulation.
- Vitamin D receptor (VDR) function is more complex than previously understood.
Purpose of the Study:
- To re-evaluate the role of 1α,25(OH)2D3 beyond its nuclear transcription factor function.
- To highlight the significance of membrane-based signaling pathways in vitamin D's biological activity.
- To propose future research directions focusing on vitamin D's interaction with membrane signaling and intercellular communication.
Main Methods:
- Review of existing studies on 1α,25(OH)2D3 and its effects on signaling pathways.
- Analysis of paracrine mechanisms involving cytokine and growth factor secretion.
- Consideration of post-transcriptional and post-translational modifications.
- Proposal for utilizing global analyses like RNA-Seq, transcriptomic arrays, and genome-wide ChIP.
Main Results:
- 1α,25(OH)2D3 modulates plasma membrane signaling pathways activated by growth factors and cytokines.
- Vitamin D influences gene expression through paracrine mechanisms.
- Non-genomic and post-transcriptional/translational effects contribute significantly to 1α,25(OH)2D3 activity.
- VDR's role extends to membrane-associated signaling.
Conclusions:
- The biological activity of 1α,25(OH)2D3 is significantly mediated by interactions with membrane-based signaling pathways.
- Vitamin D's role in intercellular communication through paracrine factor modulation is crucial.
- Future research should prioritize investigating the interplay between 1α,25(OH)2D3, membrane signaling, and cell-to-cell communication.
- Advanced genomic and molecular techniques are essential for dissecting these complex interactions.
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