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
