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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158 SUSAN WRAY AND THEODOR BURDYGA<br />
b<strong>in</strong>d<strong>in</strong>g sites are vacant (700). The proton countertransport<br />
has been reported to stop around lum<strong>in</strong>al pH 8.0<br />
(551). Thus it may be anticipated that pH will affect<br />
SERCA Ca pump<strong>in</strong>g. Grover’s group have studied the<br />
effects of pH alteration on SERCA activity <strong>in</strong> a variety of<br />
smooth muscle preparations and concluded that alkal<strong>in</strong>ization<br />
decreased its activity and acidification <strong>in</strong>creased it<br />
(165, 166, 228). As a decrease <strong>in</strong> pH <strong>in</strong>hibits k<strong>in</strong>ase activity,<br />
then phosphorylation of phospholamban will be reduced,<br />
which <strong>in</strong> turn will produce a decrease <strong>in</strong> SERCA<br />
activity (606). Stimulation of SOCE, by SR Ca depletion,<br />
has also been reported to be pH sensitive and contribute<br />
to the effects of pH o on vascular tone (748).<br />
Thus, although sometimes overlooked as <strong>in</strong>vestigators<br />
focus on ion channels and changes <strong>in</strong> myofilament Ca<br />
sensitivity, effects of pH alterations on Ca release and<br />
SERCA activity <strong>in</strong> smooth muscles will be significant<br />
factors <strong>in</strong> functional changes.<br />
C. Metabolism<br />
Here we address how metabolic changes such as<br />
ATP, phosphocreat<strong>in</strong>e (PCr), and P i levels affect SERCA<br />
activity. Most methods of determ<strong>in</strong><strong>in</strong>g SERCA activity<br />
couple its cycl<strong>in</strong>g to ATP hydrolysis via measurements of<br />
NADH, with the rate of NADH disappearance be<strong>in</strong>g proportional<br />
to the rate of ATP hydrolysis by SERCA (414).<br />
Other approaches target the production of P i by SERCA<br />
activity <strong>in</strong> colorimetric-based assays (e.g., Ref. 109). In a<br />
recent paper, Williams et al. (762) described an HPLCbased<br />
method that also measured ATP, ADP, and PCr.<br />
The SERCA activity is calculated from the changes <strong>in</strong> ATP<br />
and ADP. The authors were also able to confirm that the<br />
PCr is used locally via creat<strong>in</strong>e k<strong>in</strong>ase to synthesize local<br />
ATP for SERCA (244, 366). Thus functional coupl<strong>in</strong>g and<br />
localization between PCr, creat<strong>in</strong>e k<strong>in</strong>ase, and SERCA<br />
occurred. This specific b<strong>in</strong>d<strong>in</strong>g of creat<strong>in</strong>e k<strong>in</strong>ase to<br />
SERCA had previously been reported (e.g., Refs. 367,<br />
598). As PCr levels are much lower <strong>in</strong> smooth compared<br />
with striated muscles (385, 659, 773), this position<strong>in</strong>g of<br />
creat<strong>in</strong>e k<strong>in</strong>ase by the SERCA membrane may be particularly<br />
useful <strong>in</strong> smooth muscles. Local metabolic<br />
control of SERCA may be advantageous dur<strong>in</strong>g conditions<br />
of metabolic stress, <strong>in</strong> ma<strong>in</strong>ta<strong>in</strong><strong>in</strong>g SERCA function<br />
and prevent<strong>in</strong>g cytoplasmic [Ca] from becom<strong>in</strong>g<br />
too high.<br />
Investigators have suggested, based on the location<br />
of glycolytic enzymes, that there is also a coupl<strong>in</strong>g between<br />
glycolysis and SERCA activity (168, 780). In smooth<br />
muscle, a large body of work, particularly from Lorenz<br />
and Paul (410), has led to the theory of metabolic compartmentation.<br />
Although beyond the scope of this review,<br />
there is good evidence that ATP, provided by oxidative<br />
phosphorylation, supports contraction, whereas that from<br />
Physiol Rev VOL 90 JANUARY 2010 www.prv.org<br />
glycolysis supports membrane pumps <strong>in</strong> smooth muscle<br />
(246, 295, 420, 421). There is also a much greater lactate<br />
production and use of glycolysis under normoxic conditions<br />
<strong>in</strong> smooth muscle compared with many other cell<br />
types (422, 770). Dur<strong>in</strong>g hypoxia or ischemia, effects of<br />
pH and changes <strong>in</strong> metabolites on SERCA activity will be<br />
expected to contribute to contractile dysfunction (683).<br />
XIV. MATHEMATICAL MODELING<br />
Given the accepted complexities of SR Ca uptake and<br />
release events, and their reciprocal effect on cytoplasmic<br />
[Ca], plasmalemmal ion channels, and other organelles<br />
such as the mitochondria, there is merit <strong>in</strong> develop<strong>in</strong>g<br />
models of E-C coupl<strong>in</strong>g <strong>in</strong> smooth muscle cells. One<br />
considerable obstacle to the use of such models is the<br />
lack of quantitative data for many of the essential parameters,<br />
e.g., SR [Ca]. Even sett<strong>in</strong>g aside experimental differences<br />
such as temperature, species, and stimulation<br />
mode, for some smooth muscles, e.g., urethra and anococcygeus,<br />
many necessary measurements are simply not<br />
available; others such as vascular and uter<strong>in</strong>e smooth<br />
muscles have been better studied.<br />
There are several mathematical models of various<br />
aspects of E-C coupl<strong>in</strong>g <strong>in</strong> smooth muscle now available<br />
[e.g., airway, (376), mesenteric artery (335), cerebral artery<br />
(786)]. Other models have addressed more general<br />
questions, such as superficial buffer barrier (37), slow<br />
waves (289), prote<strong>in</strong> <strong>in</strong>teractions (171), and IP 3 changes<br />
(176). The use of such models could provide significant<br />
<strong>in</strong>sight <strong>in</strong>to the work<strong>in</strong>gs of the SR by tak<strong>in</strong>g an <strong>in</strong>tegrated<br />
approach. As such models become more detailed and SR<br />
focussed, and the “miss<strong>in</strong>g” parameters are experimentally<br />
determ<strong>in</strong>ed, then a better overall description and<br />
understand<strong>in</strong>g of the SR <strong>in</strong> different smooth muscles<br />
should emerge.<br />
XV. CONCLUSIONS AND FUTURE DIRECTIONS<br />
The SR is vital to the modulation and regulation of<br />
force <strong>in</strong> smooth muscles. Pathophysiologies are associated<br />
with perturbation of SERCA, Ca release mechanisms,<br />
and regulatory prote<strong>in</strong>s, but our appreciation of<br />
this lags beh<strong>in</strong>d studies on striated muscles. This can<br />
largely be attributed to the lack of clarity around the<br />
regulation of normal SR function <strong>in</strong> smooth muscle,<br />
which <strong>in</strong> turn is affected by genu<strong>in</strong>e differences between<br />
tissues. It is uncommon for <strong>in</strong>vestigators to address more<br />
than one smooth muscle <strong>in</strong> their studies, lead<strong>in</strong>g to pockets<br />
of detailed <strong>in</strong>formation <strong>in</strong> specific areas, but a lack of<br />
breadth. There are areas where real progress has been<br />
made, such as unravel<strong>in</strong>g the Ca spark-STOC mechanism<br />
of regulat<strong>in</strong>g excitability and function. Other areas rema<strong>in</strong><br />
controversial, such as the role of TRPCs <strong>in</strong> store-operated