Friday, October 10, 2014

Calcineurin regulation of Ca2+ sparks in airway smooth muscle cells

Hope you have had a great summer. And I am certain that your summer reading list has included every issue of AJP Lung with exciting stories and thrilling science that makes you want to be an author as well!

I want to bring your attention to a recent paper by Savoia et al. (AJPL 2014, Sept 19, PMID:25239916) on calcineurin regulation of Ca2+ sparks in airway smooth muscle cells. Those of us in the smooth muscle and Ca regulation worlds have been fascinated by those tiny, localized bursts of Ca2+ that do more than just look pretty on high speed confocal imaging movies. Studies in different cell types have shown that sparks can regulate membrane potential (and thus indirectly affect intracellular Ca2+ and contractility) as well as modulate signaling intermediates in skeletal, cardiac and smooth muscles. It is now well-established that sparks represent localized sarcoplasmic Ca2+ release from groups of ryanodine receptors (RyRs), with the receptor isoform composition differing between cell types, and sometimes even within a cell. What is now being increasingly recognized is that RyR-mediated Ca2+ sparks are highly regulated in themselves, beyond the usual “Ca2+ induced Ca2+ release” mechanism that involves Ca2+ release via IP3 receptor (IP3R) that then activates RyR channels due to changes in the local Ca2+ environment. Such regulation has been shown to involve protein kinases for example.  
In the paper by Savoia et al., the authors report on a novel regulatory mechanism that is not dependent on IP3R, but involves the Ser/Thr protein phosphatase calcineurin (CaN). The authors show that CaN upregulates Ca2+ spark activity in airway smooth muscle cells and that a CaN inhibitor peptide (CAIP) can blunt sparks. Such effects are entirely intracellular, and do not involve Ca2+ influx or IP3R mediated local Ca2+ release. Importantly, CaN appears to regulate only RyR1 (the “skeletal” isoform), but not RyR2 or RyR3, when airway smooth muscle usually expresses all three isoforms. For me, the importance of this novel regulatory pathway is at least twofold. 

First, one could ask the question: what is the role of RyR1 per se in ASM Ca2+ and contractility, particularly in the context of inflammation or diseases such as asthma which show increased airway contractility? If, as some studies suggest, RyR1 is a key isoform, then CaN regulation that is specific to this isoform becomes quite significant as an avenue to modulate contractility. However, surprisingly, there is currently no information on changes in RyR expression patterns of smooth muscle in asthma, and thus points to at least one avenue for future research. 

Second, one should ask the question: what is the role of CaN in asthma? There is much interest in the use of calcineurin/NFAT modulators for atopy and allergy, particularly in the context of T-cell modulation, but there is again surprisingly, little to no information on how CaN could influence airway smooth muscle. The novel findings of Savoia et al. suggest at least one mechanism, that may then lead to further modulation of long-term consequences of altered intracellular Ca2+, including cell proliferation. 

Overall, I see the paper by Savoia et al. as a nice launchpad to start exploring the role of CaN in airway smooth muscle in the context of contractility and other functions of this cell type, particularly in the context of asthma.  

Regards, Y.S. Prakash

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