Sarcoplasmic Reticulum Function in Smooth Muscle - Physiological ...
Sarcoplasmic Reticulum Function in Smooth Muscle - Physiological ...
Sarcoplasmic Reticulum Function in Smooth Muscle - Physiological ...
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120 SUSAN WRAY AND THEODOR BURDYGA<br />
Many of the features that led to the postulation of a<br />
specialized space and environment between the SR and<br />
plasma membrane will also hold for regions between the<br />
SR and other organelles.<br />
4. Superficial buffer barrier<br />
Van Breemen and colleagues (713, 715) hypothesized<br />
<strong>in</strong> the 1980s that there is a subplasmalemmal doma<strong>in</strong> that<br />
is functionally separated from the cytosolic constituents<br />
by the superficial SR and that this would be important <strong>in</strong><br />
modulat<strong>in</strong>g Ca signal<strong>in</strong>g and force production <strong>in</strong> smooth<br />
muscle. This peripheral SR, be<strong>in</strong>g so close to the sites of<br />
Ca entry, would act to scavenge and buffer extracellular<br />
Ca entry. This buffer<strong>in</strong>g ability would be overcome dur<strong>in</strong>g<br />
agonist stimulation or depolarization but could act to help<br />
ma<strong>in</strong>ta<strong>in</strong> rest<strong>in</strong>g [Ca] low between stimuli. Follow<strong>in</strong>g<br />
stimulation, the superficial SR will release Ca back to the<br />
plasma membrane Ca extrusion mechanisms. Because of<br />
the difficulty of directly measur<strong>in</strong>g [Ca] <strong>in</strong> microdoma<strong>in</strong>s,<br />
direct experimental support for them was lack<strong>in</strong>g. However,<br />
with the advent of near-membrane Ca <strong>in</strong>dicators<br />
(170, 809), evidence support<strong>in</strong>g or consistent with the<br />
superficial buffer barrier role of the SR <strong>in</strong> smooth muscles<br />
has been provided <strong>in</strong> a variety of preparations [vascular<br />
(587, 713), gastric (754), bladder (789), uterus (631, 793)].<br />
The sites on the SR of Ca release and uptake dur<strong>in</strong>g these<br />
processes may be functionally and spatially separate<br />
(635). The estimates of subplasmalemma [Ca] have been<br />
between 10 and 50 M [gastric (170), colonic (77), arterial<br />
(809)], and the elevations of [Ca] last up to 100–200 ms<br />
(339).<br />
Inhibition of SERCA <strong>in</strong>creases bulk Ca signals produced<br />
<strong>in</strong> response to agonists, which is consistent with<br />
the superficial buffer barrier hypothesis. Bradley et al.<br />
(77) calculated that the buffer accounted for b<strong>in</strong>d<strong>in</strong>g of<br />
50% of the Ca enter<strong>in</strong>g colonic myocytes. Recently however,<br />
this group has argued that the SR should be viewed<br />
more as a “Ca trap” and that SERCA activity cannot<br />
curtail the rise of cytosolic [Ca] but rather contributes to<br />
its decl<strong>in</strong>e when efflux ends (451; see also Ref. 635).<br />
Although not generally considered <strong>in</strong> accounts of<br />
smooth muscle microdoma<strong>in</strong>s, a role for calmodul<strong>in</strong> <strong>in</strong><br />
contribut<strong>in</strong>g to localiz<strong>in</strong>g Ca signals has been proposed<br />
(764). This arises from the f<strong>in</strong>d<strong>in</strong>g that, even at low [Ca],<br />
a specific “contractile” pool of calmodul<strong>in</strong> with zero or<br />
two of its four Ca-b<strong>in</strong>d<strong>in</strong>g sites occupied is tightly bound<br />
to the contractile mach<strong>in</strong>ery. Local changes of [Ca] near<br />
the myofilaments could then activate this specific calmodul<strong>in</strong><br />
pool by saturat<strong>in</strong>g the four Ca-b<strong>in</strong>d<strong>in</strong>g sites to activate<br />
myos<strong>in</strong> light-cha<strong>in</strong> k<strong>in</strong>ase (MLCK) and cause contraction,<br />
while more distant local [Ca] changes need not<br />
be associated with contraction (764).<br />
E. SR and the Mitochondria<br />
Physiol Rev VOL 90 JANUARY 2010 www.prv.org<br />
Both EM and confocal imag<strong>in</strong>g studies have shown<br />
the SR and mitochondrial membranes to be <strong>in</strong> very close<br />
proximity (175, 677). The distance between them may be<br />
as small as 10 nm (515). As with caveolae, the SR may<br />
appear to engulf mitochondria, and thereby create a specialized<br />
space for Ca signal<strong>in</strong>g, discussed below. Although<br />
close association between ER and mitochondria has been<br />
described <strong>in</strong> other cell types (489, 561), few have reported<br />
the almost complete envelop<strong>in</strong>g, which appears to be a<br />
feature of smooth muscles. This aspect has been exam<strong>in</strong>ed<br />
<strong>in</strong> detail at the EM level by Dai et al. (140) <strong>in</strong> pig<br />
tracheal muscle. At rest, all (99.4%) mitochondria were<br />
with<strong>in</strong> 30 nm of SR membrane, and the average distance<br />
was 22 nm. The majority (82%) of mitochondria were<br />
completely encircled or enwrapped by the SR network.<br />
The regions of close contact lacked the regular spac<strong>in</strong>g<br />
sometimes seen between SR and plasma membrane, but<br />
specific anchors have been suggested <strong>in</strong> other cell types<br />
(175, 241).<br />
What makes the above data particularly <strong>in</strong>terest<strong>in</strong>g is<br />
that the association of mitochondria and SR changed with<br />
acetylchol<strong>in</strong>e (ACh) stimulation. The number of mitochondria<br />
surrounded by SR fell to 12%, and fewer were <strong>in</strong><br />
close contact. The authors suggest the SR unwraps from<br />
mitochondria with stimulation and extends more <strong>in</strong>to the<br />
cytoplasm. These structural arrangements between SR<br />
and mitochondria have been reported <strong>in</strong> Mad<strong>in</strong>-Darby<br />
can<strong>in</strong>e kidney (MDCK) II cells, but it is elevated [Ca] that<br />
keeps the close association and between them and low<br />
[Ca] causes dissociation (735). Lateral movements of mitochondria<br />
relative to the SR of up to 3 m/s have been<br />
reported <strong>in</strong> neuroblastoma cells (405).<br />
1. Mitochondria and smooth muscle Ca signal<strong>in</strong>g<br />
There is now a large amount of literature on mitochondrial<br />
Ca signal<strong>in</strong>g and the <strong>in</strong>teractions between the<br />
SR and mitochondria. It is beyond the scope of this review<br />
to assess all the literature on mitochondrial Ca signal<strong>in</strong>g,<br />
but we will give an account of recent data <strong>in</strong>vestigat<strong>in</strong>g<br />
SR-mitochondrial signal<strong>in</strong>g <strong>in</strong> smooth muscle. The follow<strong>in</strong>g<br />
reviews provide a good perspective on this area (296,<br />
451, 565).<br />
Mitochondrial Ca uptake has enjoyed a resurgence of<br />
<strong>in</strong>terest (53) largely accounted for by new techniques<br />
allow<strong>in</strong>g for monitor<strong>in</strong>g their role <strong>in</strong> Ca signal<strong>in</strong>g and the<br />
weight of accumulated evidence show<strong>in</strong>g that Ca uptake<br />
occurs dur<strong>in</strong>g physiological conditions (e.g., Refs. 49, 159,<br />
590). Due to the low aff<strong>in</strong>ity of their Ca transporter (46),<br />
the capacity of mitochondria to rapidly accumulate Ca<br />
was considered only relevant dur<strong>in</strong>g pathologically high<br />
[Ca]. That there could be microdoma<strong>in</strong>s of high [Ca]<br />
around mitochondria, to which the SR (or ER) would