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. Author manuscript; available in PMC: 2016 Mar 1.
Published in final edited form as: J Steroid Biochem Mol Biol. 2014 Nov 6;0:81–84. doi: 10.1016/j.jsbmb.2014.11.002

Membrane-mediated Actions of 1,25-Dihydroxy Vitamin D3: A Review of the Roles of Phospholipase A2 Activating Protein and Ca2+/Calmodulin-dependent Protein Kinase II

Maryam Doroudi a, Zvi Schwartz b,d, Barbara D Boyan a,b,c,*
PMCID: PMC4323845  NIHMSID: NIHMS640890  PMID: 25448737

Abstract

The secosteroid 1α,25-dihydroxy vitamin D3 [1α,25(OH)2D3] acts on cells via classical steroid hormone receptor-mediated gene transcription and by initiating rapid membrane-mediated signaling pathways. In its membrane-initiated pathway, after 1α,25(OH)2D3 interacts with protein disulfide isomerase, family A, member 3 (Pdia3) in caveolae, phospholipase A2 (PLA2) and protein kinase C (PKC) are activated. Recent efforts to determine the signaling proteins involved in the 1α,25(OH)2D3 signal from Pdia3 to PLA2 have indicated that phospholipase A2 activating protein (PLAA) and Ca2+/calmodulin-dependent kinase II (CaMKII) are required. PLAA is located in caveolae, where it interacts with Pdia3 and caveolin-1 (Cav-1) to initiate rapid signaling via CaMKII, activating PLA2, leading to activation of protein kinase C (PKC) and PKC-dependent responses.

Keywords: 1α,25(OH)2D3; PDIA3; PLA2; PLAA; Protein Kinase C; Ca2+/calmodulin-dependent protein kinase II

1. Introduction

The vitamin D metabolite 1α,25-dihydroxy vitamin D3 [1α,25(OH)2D3] is known to play an important role in controlling extracellular Ca2+ homeostasis, regulating development of the cartilaginous growth plate and modulating bone growth and metabolism (1–5). 1α,25(OH)2D3 regulates musculoskeletal cells via two different mechanisms: classical steroid hormone receptor dependent gene transcription, and rapid membrane-initiated signaling (6–8). 1α,25(OH)2D3 selectively interacts with two identified receptors, the nuclear vitamin D receptor (VDR) and membrane-associated protein disulfide isomerase, family A, member 3 (Pdia3), to modulate cell functions via membrane-associated signaling pathways (9).

We have used cartilage and bone cell models to understand how Pdia3 mediates rapid responses to 1α,25(OH)2D3. Growth zone chondrocytes (GC) isolated from the rat costochondral growth plate and MC3T3-E1 mouse osteoblasts respond to 1α,25(OH)2D3 with a rapid increase in activities of phospholipase A2 (PLA2), phospholipase Cβ (PLCβ) and protein kinase C alpha (PKCα) and PGE2 release (10,11).

Pdia3 is present in caveolae and caveolae are required for the membrane functions of 1α,25(OH)2D3 (12). The caveolae plasma membrane microdomains are characterized by presence of caveolin-1 (Cav-1), caveolin-2 (Cav-2), and caveolin-3 (Cav-3). GC chondrocytes isolated from Cav-1 knockout (Cav-1−/−) mice and Cav-1 silenced osteoblasts are not capable of initiating the rapid PKC activation response to 1α,25(OH)2D3 (12).

Figure 1 summarizes our findings demonstrating the critical role Pdia3 and the caveolae microenvironment in mediating the effects of 1α,25(OH)2D3 on PKC. Rapid actions of 1α,25(OH)2D3 in MC3T3-E1 cells can be blocked by antibodies to Pdia3 (data not shown), or by silencing either Pdia3 or Cav-1. However, rapid activation of PKC is seen in VDR-silenced MC3T3-E1 cells, indicating that the VDR is not required.

Figure 1.

Figure 1

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Effects of Pdia3, Vdr and Cav-1 silencing on 1α,25(OH)2D3-stimulated PKC activation in MC3T3-E1 osteoblasts. The data show treatment vs. vehicle ratios. *p<0.05, vs. vehicle; $p<0.05, vs. 1α,25(OH)2D3 treated WT.

We have reported that PLA2 activating protein (PLAA) stimulates PLA2 activation. Moreover, the effects of PLAA mimic the effects of 1α,25(OH)2D3 treatment on GC chondrocytes and MC3T3-E1 osteoblasts, suggesting that PLAA acts upstream of PLA2 in 1α,25(OH)2D3 membrane-mediated signaling (11,13). Recent studies also demonstrated that activation of Ca2+/calmodulin-dependent kinase II (CaMKII) is required for the actions of PLA2 (14). Collectively, these data indicate that PLAA and CaMKII are required for 1α,25(OH)2D3 rapid membrane-mediated signaling but they don’t clarify the relationship between PLAA and CamKII. This review will focus on the role of PLAA in mediating 1α,25(OH)2D3-stimulated Pdia3-dependent events at the plasma membrane. It will also demonstrate the importance of CaMKII in mediating rapid activation of PLA2 in response to 1α,25(OH)2D3. Finally, this review will provide crucial evidence that 1α,25(OH)2D3 stimulates PLA2 via PLAA and CaMKII, a process initiated by Pdia3/PLAA interaction, which further triggers CaMKII-dependent PLA2 activation.

2. Role of PLAA

There is now a considerable body of evidence indicating that PLA2 plays an important role in 1α,25(OH)2D3–activated membrane-mediated signaling (13,15–18). Melittin and mastasparan are stimulators of PLA2 that have exhibited similar effects to those of 1α,25(OH)2D3 on PLCβ and PKCα activation (19). In contrast, AACOCF3, OEPC and quinacrine, which inhibit PLA2 activity, antagonize the stimulatory effects of 1α,25(OH)2D3, placing activation of PLA2 upstream of PLCβ and PKCα (11,19). Despite accumulating experimental evidence indicating the activation of PLA2 as one of the early events in 1α,25(OH)2D3–activated membrane-mediated signaling, the signaling molecules linking Pdia3 to PLA2 remained unidentified.

Human PLAA was reported to have a region of 38% homology with melittin (20), raising the possibility that it was responsible for activation of PLA2 in response to 1α,25(OH)2D3. To test this hypothesis, we first determined that GC chondrocytes express mRNAs for PLAA (13). The presence of PLAA mRNA in cells sensitive to 1α,25(OH)2D3 was demonstrated in the growth zone of rat growth plates by in situ hybridization (13). We subsequently showed that PLAA interacts with Pdia3 receptor complex (21).

To elucidate the role of PLAA in rapid actions of 1α,25(OH)2D3, we studied the effects of Plaa silencing in osteoblastic MC3T3-E1 cells. Silencing Plaa led to a significant reduction in CaMKII and PLA2 activity in response to 1α,25(OH)2D3 treatment (21) (Fig. 2). PLA2 activation generates arachidonic acid (AA), which is processed further to PGE2 (19,22). As expected, ShPlaa MC3T3-E1 osteoblasts failed to rapidly release PGE2 in response to 1α,25(OH)2D3 (21). AA can also stimulate PKCα activity directly (23). Additionally, Gαq and lysophospholipid activate phosphatidylinositol-specific PLCβ, producing diacylglycerol (DAG) and inositol 1,4,5-trisphosphate (IP3) (19,24). The binding of DAG to PKCα induces its recruitment to the plasma membrane (25). IP3-activated Ca2+ release from the endoplasmic reticulum is required for PKCα activation. Similar to our previous findings, shPlaa osteoblasts also failed to activate PKC in response to 1α,25(OH)2D3 (21). In agreement with results of studies using ShPlaa cells, PLAA-antibody blocked the actions of PLAA protein and consequently suppressed 1α,25(OH)2D3-stimulated PKC activation in GC and MC3T3-E1 cells (21).

Figure 2.

Figure 2

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Effects of Plaa silencing on CaMKII, PLA2 and PKC activation, and PGE2 release in MC3T3-E1 osteoblast in response to 1α,25(OH)2D3. The data show treatment vs. vehicle ratios. The dashed line represents the vehicle control (dashed line=1). *p<0.05, treatment vs. control; #p<0.05, WT vs. ShPlaa.

Figure 2 summarizes our findings with respect to the role of PLAA in the rapid response of osteoblasts to 1α,25(OH)2D3 treatment. Silencing Plaa in MC3T3-E1 cells prevents activation of CaMKII, PLA2 and PKC, as well as release of PGE2. Moreover, our biochemical studies confirmed the subcellular localization of PLAA and its protein interacting partners. PLAA and Pdia3 receptor were present in plasma membranes and caveolae of GC cells and MC3T3-E1 cells (21). Immunoprecipitation studies showed that PLAA’s interaction with Cav-1 did not change with 1α,25(OH)2D3 treatment; however, Pdia3 interacted with PLAA only after 1α,25(OH)2D3 treatment (21). This finding supports the hypothesis that PLAA is a crucial mediator of 1α,25(OH)2D3 signaling, which aids in transducing the signal from Pdia3 to PLA2.

3. Role of CaMKII

Although we demonstrated that the rapid response to 1α,25(OH)2D3 requires the presence of PLAA (21), the mechanism underlying how PLAA mediated the signal from Pdia3 to PLA2 remained unanswered. 1α,25(OH)2D3 mediates its actions via a cascade of Ca2+-dependent pathways in which Ca2+ is released from intracellular stores or basal lateral membrane Ca2+ channels (6,26–28). The rise in intracellular Ca2+ is associated with activation of Ca2+ sensitive kinases including PKC, the ERK1/2 family of mitogen activated protein kinases (MAPK), and CaMKII. Recently, CaMKII was identified as one of the regulators of PLA2 activity (14). The CaMKII inhibitor, KN-93 and CaMKII antisense oligonucleotide suppressed norepinephrine-stimulated PLA2 activation and arachidionic acid release in vascular smooth muscle cells. This led us to hypothesize that CaMKII is a likely candidate for mediating the 1α,25(OH)2D3 signal from PLAA to PLA2.

To investigate the role of CaMKII in rapid actions of 1α,25(OH)2D3, we studied the effects of silencing Camk2a, the gene encoding CaMKII isoform α in osteoblastic MC3T3-E1 cells (29). Silenced Camk2a (ShCamk2a) MC3T3-E1 cells failed to rapidly activate CaMKII in response to 1α,25(OH)2D3 (29). In contrast, silencing Camk2b, which encodes the CaMKII isoform β did not significantly reduce CaMKII activity in response to 1α,25(OH)2D3 (data not shown). Collectively, these findings suggest that CaMKII mediates 1α,25(OH)2D3 signal in an isoform-specific manner. Silencing Camk2a significantly reduced PLA2 and PKC activities and PGE2 release in response to 1α,25(OH)2D3. In agreement with these results, the CaMKII inhibitors myristoylated calmodulin kinase IINtide (mer-CaMKIINtide) and KN-93 abrogated 1α,25(OH)2D3-stimulated PLA2 and PKC activities and PGE2 release (data not shown) (29–31).

The experiments summarized in Figure 3 demonstrate the important role of CaMKII in the signaling pathway initiated by 1α,25(OH)2D3. Silencing Camk2a prevents activation of PLA2 and PKC, as well as the release of PGE2. These experiments also implicate CaMKII in mediated the signal from PLAA to PLA2, as depicted in Figure 4 and discussed below.

Figure 3.

Figure 3

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Effects of Camk2a silencing on CaMKII, PLA2 and PKC activation, and PGE2 release in MC3T3-E1 osteoblast cells. The data show treatment vs. vehicle ratios. The dashed line represents the vehicle control (dashed line=1). *p<0.05, treatment vs. control; #p<0.05, WT vs. ShCamk2a.

Figure 4.

Figure 4

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Overview of 1α,25(OH)2D3 membrane-mediated pathway.

4. Overview of 1α,25(OH)2D3 Membrane-mediated Pathway

The studies reviewed here show the roles of PLAA and CaMKII in initiating rapid actions of 1α,25(OH)2D3 at the plasma membrane (Figure 4). The binding of 1α,25(OH)2D3 to the Pdia3 receptor stimulates the interaction between PLAA and Pdia3 protein complexes in caveolae microdomains, leading to activation of CaMKII. Subsequently, PLA2 is activated initiating rapid release of AA. AA mediates its effects activating PKC directly, or it is further metabolized by cyclooxygenase I to producing PGE2, which binds its EP1 receptor resulting in downstream activation of PKC.

5. CONCLUSIONS

1α,25(OH)2D3 membrane-activated responses are mediated by PLAA, which is present in caveolae where it physically interacts with Pdia3 to initiate rapid responses. CaMKII isoform α is required for mediating the rapid actions of 1α,25(OH)2D3 from PLAA to PLA2. Both PLAA and CaMKII play crucial roles in mediating the Ca2+-dependent actions of 1α,25(OH)2D3 suggesting their possible fundamental role in mediating other Ca2+-dependent pathways. This review has focused on rapid activation of the PKC signaling pathway, which did not require VDR. However, VDR is involved in other rapid actions of the secosteroid, particularly with respect to Ca++ transport across the cell membrane (32).

Highlights.

  • Silencing Camk2a inhibits 1α,25(OH)2D3-stimulated PLA2 and PKC activation.

  • Silencing Plaa inhibits 1α,25(OH)2D3-stimulated CaMKII, PLA2 and PKC activation.

  • 1 α,25(OH)2D3 membrane signaling acts via rapid activation of PLAA.

  • PLAA activates CaMKII, PLA2 and PKC, arachidonic acid release and PGE2 production.

Acknowledgments

This research was supported by grants from the Price Gilbert, Jr. Foundation and Children’s Healthcare of Atlanta.

Footnotes

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