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Logo of nihpaAbout Author manuscriptsSubmit a manuscriptHHS Public Access; Author Manuscript; Accepted for publication in peer reviewed journal;
Circ Res. Author manuscript; available in PMC 2010 July 2.
Published in final edited form as:
PMCID: PMC2746038

Calcineurin Finds a New Partner in the L-type Ca2+ Channel

Calcineurin is a Ca2+/calmodulin-sensitive phosphatase that sits towards the top of signaling pathways leading to pathologic cardiac hypertrophy1. Pathologic stressors activate calcineurin, for which nuclear factor of activated T-cells (NFAT) is a principal substrate. Dephosphorylation unmasks a nuclear localization signal on NFAT, which then translocates to the nucleus and there serves as part of a transcription factor complex able to initiate gene expression cascades that induce cardiac hypertrophy and subsequent heart failure. Determining how calcineurin is specifically activated in response to hypertrophic stressors by the same Ca2+ signal utilized for excitation-contraction coupling has been a major challenge. Triggered by Ca2+ influx through CaV1.2 voltage-gated Ca2+ channels at the sarcolemmal membrane, intracellular calcium briefly rises ten-fold with each heart beat to generate myocyte contraction. Almost as quickly intracellular calcium falls to its baseline level, allowing myocyte relaxation and preparation for the next beat.

There are two leading proposals for how Ca2+ could activate the calcineurin/NFAT pathway—or function as a versatile regulator of multiple other signaling cascades—in the face of the large Ca2+ oscillations driving each cycle of contraction and relaxation. One is that modulation of the amplitude and/or frequency of the oscillatory contractile Ca2+ signal triggers particular Ca2+ sensors that then activate particular downstream signaling pathways, such as calcineurin activation.2 The alternative suggests that local Ca2+ signaling microdomains, secluded from the contractile oscillations, feed into specific signaling cascades, such as calcineurin activation.3, 4 In this issue Tandan et al.5 propose that calcineurin binds directly to the sarcolemmal CaV1.2 voltage-gated Ca2+ channel and thereby modulates its function. By localizing calcineurin at the site of the major source of Ca2+ entry, this report could provide more support for the Ca2+ signaling microdomain hypothesis and offer a new wrinkle into the understanding of hypertrophic signaling.

We already knew that the CaV1.2 Ca2+ channel and calcineurin could reside in the same neighborhood. In neurons, for example, the A-kinase anchoring protein AKAP79/150 has been shown to act as a scaffold for both the CaV1.2 channel and calcineurin.6 CaV1.2 also functions as part of a complex with PKCα and calcineurin in vascular smooth muscle cells; here AKAP79/150 is also thought to be the scaffold7. In both cases the coupled calcineurin activates NFAT via Ca2+ influx through CaV1.2. Now, Tandan et al.5 report that in cardiac myocytes calcineurin and CaV1.2 can shed their AKAP chaperone and cohabitate. They identify direct calcineurin binding sites on the CaV1.2 N and C termini. Nevertheless, CaV1.2 is a strange bedfellow. Both calcineurin binding sites—the one most extensively characterized in the distal C terminus (amino acids 1943-1971) and another, unidentified site in the N terminus—lack a consensus VIVIT-like motif found in many validated calcineurin binding proteins such as NFAT8 and AKAP79/150.9 Tandan et al. also report that the interaction with the CaV1.2 C terminus renders the channel a calcineurin substrate and that calcineurin reverses PKC phosphorylation. Thus, this report may define a new calcineurin interaction motif and a novel mode of action.

A particularly notable finding is that calcineurin positively regulates CaV1.2 in neonatal myocytes. Although adenoviral overexpression of calcineurin increased CaV1.2 currents,5 consistent with previous reports that calcineurin-induced hypertrophy augmented CaV1.2 currents in myocytes,10, 11 none of these experiments distinguished if calcineurin directly potentiated the CaV1.2 currents or if the increased current amplitude was an indirect outcome of the resulting cellular hypertrophy. Here, Tandan et al.5 report that calcineurin inhibition (via cyclosporin) induced an immediate and partially reversible potentiation of CaV1.2 currents in neonatal myocytes. The rapidity and reversibility of these effects suggest a direct effect of calcineurin on CaV1.2 rather than transcriptional regulation via actions on NFAT. The potentiating effects of calcineurin on CaV1.2 in neonatal myocytes are surprising, however, since a recent study suggest that the predominant effect of phosphorylation on cardiac CaV1.2 by PKC, which calcineurin is proposed to antagonize, is potentiation.12 This mechanism of action for calcineurin also provides a stark contrast to that reported in neurons6, where AKAP79/150-bound calcineurin opposes potentiation of CaV1.2 by PKA. In neonatal myocytes Tandan et al. found that neither adenoviral overexpression of calcineurin nor RCAN1 (a calcineurin inhibitor) affected isoproterenol-stimulated increase in CaV1.2 current amplitude. Thus, the specific means by which calcineurin produces this intriguing rapid and reversible CaV1.2 potentiation are not yet apparent.

So, does this CaV1.2-bound calcineurin with newly defined properties activate NFAT, as the AKAP-bound calcineurin does in neurons6, and does the channel-phosphatase complex participate in the hypertrophic signaling pathway? The proximity of this fundamental Ca2+-sensitive signaling molecule near the chief source of Ca2+ entry makes this an exciting possibility, but we will have to wait for follow-up studies to test this hypothesis. Although overexpression of calcineurin induced hypertrophy, as shown previously1, the authors have not yet established whether induction of hypertrophy depends upon direct binding to CaV1.2. Specific studies designed to test if calcineurin-induced hypertrophy and hypertrophy-induced NFAT activation are altered when the channel-phosphatase interaction has been disrupted will be necessary to resolve this issue. Other questions arising from this report include whether any of the intriguing potentiating effects of calcineurin on CaV1.2 Ca2+ current result from the direct binding between the two or derive from actions of another pool calcineurin untethered from the channel. Also unexplored is whether the observed CaV1.2 current potentiation is a result of calcineurin-mediated dephosphorylation of CaV1.2 or of another, intermediate substrate. Future studies will tell if the calcineurin-CaV1.2 coupling proves a fruitful partnership.


Sources of Funding: This work was supported by NIH grants HL088089 and HL071165. GSP is an Established Investigator of the American Heart Association (#0740030N).


Disclosures: None.


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