Sarcoplasmic Reticulum Function in Smooth Muscle - Physiological ...

120 SUSAN WRAY AND THEODOR BURDYGA
Many of the features that led to the postulation of a
specialized space and environment between the SR and
plasma membrane will also hold for regions between the
SR and other organelles.
4. Superficial buffer barrier
Van Breemen and colleagues (713, 715) hypothesized
in the 1980s that there is a subplasmalemmal domain that
is functionally separated from the cytosolic constituents
by the superficial SR and that this would be important in
modulating Ca signaling and force production in smooth
muscle. This peripheral SR, being so close to the sites of
Ca entry, would act to scavenge and buffer extracellular
Ca entry. This buffering ability would be overcome during
agonist stimulation or depolarization but could act to help
maintain resting [Ca] low between stimuli. Following
stimulation, the superficial SR will release Ca back to the
plasma membrane Ca extrusion mechanisms. Because of
the difficulty of directly measuring [Ca] in microdomains,
direct experimental support for them was lacking. However,
with the advent of near-membrane Ca indicators
(170, 809), evidence supporting or consistent with the
superficial buffer barrier role of the SR in smooth muscles
has been provided in a variety of preparations [vascular
(587, 713), gastric (754), bladder (789), uterus (631, 793)].
The sites on the SR of Ca release and uptake during these
processes may be functionally and spatially separate
(635). The estimates of subplasmalemma [Ca] have been
between 10 and 50 M [gastric (170), colonic (77), arterial
(809)], and the elevations of [Ca] last up to 100–200 ms
(339).
Inhibition of SERCA increases bulk Ca signals produced
in response to agonists, which is consistent with
the superficial buffer barrier hypothesis. Bradley et al.
(77) calculated that the buffer accounted for binding of
50% of the Ca entering colonic myocytes. Recently however,
this group has argued that the SR should be viewed
more as a “Ca trap” and that SERCA activity cannot
curtail the rise of cytosolic [Ca] but rather contributes to
its decline when efflux ends (451; see also Ref. 635).
Although not generally considered in accounts of
smooth muscle microdomains, a role for calmodulin in
contributing to localizing Ca signals has been proposed
(764). This arises from the finding that, even at low [Ca],
a specific “contractile” pool of calmodulin with zero or
two of its four Ca-binding sites occupied is tightly bound
to the contractile machinery. Local changes of [Ca] near
the myofilaments could then activate this specific calmodulin
pool by saturating the four Ca-binding sites to activate
myosin light-chain kinase (MLCK) and cause contraction,
while more distant local [Ca] changes need not
be associated with contraction (764).
E. SR and the Mitochondria
Physiol Rev VOL 90 JANUARY 2010 www.prv.org
Both EM and confocal imaging studies have shown
the SR and mitochondrial membranes to be in very close
proximity (175, 677). The distance between them may be
as small as 10 nm (515). As with caveolae, the SR may
appear to engulf mitochondria, and thereby create a specialized
space for Ca signaling, discussed below. Although
close association between ER and mitochondria has been
described in other cell types (489, 561), few have reported
the almost complete enveloping, which appears to be a
feature of smooth muscles. This aspect has been examined
in detail at the EM level by Dai et al. (140) in pig
tracheal muscle. At rest, all (99.4%) mitochondria were
within 30 nm of SR membrane, and the average distance
was 22 nm. The majority (82%) of mitochondria were
completely encircled or enwrapped by the SR network.
The regions of close contact lacked the regular spacing
sometimes seen between SR and plasma membrane, but
specific anchors have been suggested in other cell types
(175, 241).
What makes the above data particularly interesting is
that the association of mitochondria and SR changed with
acetylcholine (ACh) stimulation. The number of mitochondria
surrounded by SR fell to 12%, and fewer were in
close contact. The authors suggest the SR unwraps from
mitochondria with stimulation and extends more into the
cytoplasm. These structural arrangements between SR
and mitochondria have been reported in Madin-Darby
canine kidney (MDCK) II cells, but it is elevated [Ca] that
keeps the close association and between them and low
[Ca] causes dissociation (735). Lateral movements of mitochondria
relative to the SR of up to 3 m/s have been
reported in neuroblastoma cells (405).
1. Mitochondria and smooth muscle Ca signaling
There is now a large amount of literature on mitochondrial
Ca signaling and the interactions between the
SR and mitochondria. It is beyond the scope of this review
to assess all the literature on mitochondrial Ca signaling,
but we will give an account of recent data investigating
SR-mitochondrial signaling in smooth muscle. The following
reviews provide a good perspective on this area (296,
451, 565).
Mitochondrial Ca uptake has enjoyed a resurgence of
interest (53) largely accounted for by new techniques
allowing for monitoring their role in Ca signaling and the
weight of accumulated evidence showing that Ca uptake
occurs during physiological conditions (e.g., Refs. 49, 159,
590). Due to the low affinity of their Ca transporter (46),
the capacity of mitochondria to rapidly accumulate Ca
was considered only relevant during pathologically high
[Ca]. That there could be microdomains of high [Ca]
around mitochondria, to which the SR (or ER) would