Sarcoplasmic Reticulum Function in Smooth Muscle - Physiological ...

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