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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144 SUSAN WRAY AND THEODOR BURDYGA<br />
myocytes was the same irrespective of whether just IP 3R<br />
or IP 3R and RyR stores were depleted (370). The refill<strong>in</strong>g<br />
mechanisms may depend on the location of the SR. Peripherally<br />
located stores may be functionally more closely<br />
l<strong>in</strong>ked to Ca entry via SOCE channels (215), while those<br />
located centrally could be refilled from the myoplasm.<br />
Another consideration is the type of SERCA associated<br />
with each of the stores. The Ca b<strong>in</strong>d<strong>in</strong>g aff<strong>in</strong>ity (K m) for<br />
SERCA2a is 0.31 M and for SERCA2b is 0.17 M (479).<br />
SERCA2b activity can be modulated by calmodul<strong>in</strong> (229)<br />
and phospholamban (162), and aga<strong>in</strong> this could affect<br />
cross-talk between the store and plasma membrane. If<br />
different isoforms of SERCA are associated with different<br />
stores, this could expla<strong>in</strong> differences <strong>in</strong> their ability to<br />
refill the SR <strong>in</strong> the presence of different [Ca].<br />
6. Summary<br />
It seems to us, based on the current state of knowledge,<br />
that SOCE has been demonstrated <strong>in</strong> some but not<br />
all smooth muscles and that this will occur through a<br />
Stim-Orai mechanism when the channel <strong>in</strong>volved gives<br />
rise to I crac. Variations on this mechanism may occur <strong>in</strong><br />
some smooth muscles, but it rema<strong>in</strong>s to be established if<br />
these are true variations on SOCE, or different channels<br />
such as ROCs. TRPCs may contribute to variation of<br />
SOCE <strong>in</strong> smooth muscle, lead<strong>in</strong>g to decreased Ca selectivity,<br />
but this is far from certa<strong>in</strong>. More studies, both<br />
molecular and physiological, are clearly called for, and it<br />
is important to have more <strong>in</strong>formation from nonvascular<br />
myocytes. This rema<strong>in</strong>s a controversial and complex area<br />
(396) but one of some importance. The role of SOCE<br />
pathways may change with disease states, e.g., hypertension<br />
and bronchoconstriction, as well as phenotype, e.g.,<br />
changes <strong>in</strong> arterial myocytes with proliferation, migration,<br />
or contraction (396), and thus an <strong>in</strong>creased understand<strong>in</strong>g<br />
could lead to new therapeutic targets.<br />
There is little doubt that TRP channels are expressed<br />
<strong>in</strong> many smooth muscles, particularly, but not exclusively<br />
tonic ones. As discussed, this expression does not necessarily<br />
equate to SOCE function. One recent <strong>in</strong>terest<strong>in</strong>g<br />
paper has provided evidence that TRPC channels become<br />
converted to SOCE channels as Stim1 leads to their movement<br />
from non-raft (TRCP) to raft (SOCE) membrane<br />
locations (10), whereas another recent study had TRCP<br />
channels <strong>in</strong> raft doma<strong>in</strong>s not Orai1 (148). There is evidence<br />
from only a limited number of smooth muscles of<br />
I crac; whether this scarcity is due to the difficulties of<br />
record<strong>in</strong>g these t<strong>in</strong>y currents or their absence from most<br />
smooth muscles is impossible to determ<strong>in</strong>e at the moment.<br />
Studies on cultured cells are limited models for<br />
native smooth muscle cells, as the downregulation of the<br />
normal components of E-C coupl<strong>in</strong>g and changes <strong>in</strong> SOCE<br />
will distort f<strong>in</strong>d<strong>in</strong>gs (512). The recent discoveries of Orai<br />
and Stim should help better study store-operated Ca entry<br />
<strong>in</strong> all cell types. Firm conclusions must await the ability to<br />
demonstrate store-operated entry under physiological<br />
conditions, e.g., agonist depletion, along with direct measures<br />
of lum<strong>in</strong>al SR Ca content. It is worth not<strong>in</strong>g that <strong>in</strong><br />
cardiac muscle where the SR plays a dom<strong>in</strong>ant role <strong>in</strong> E-C<br />
coupl<strong>in</strong>g, no such SOCE mechanism exists. Perhaps <strong>in</strong><br />
those smooth muscles <strong>in</strong> which Ca entry is the dom<strong>in</strong>ant<br />
feature of force production, SOCE will also not be important.<br />
In contrast, <strong>in</strong> those smooth muscles that are more<br />
reliant on SR Ca contributions to contraction and have<br />
significant neurohormonal stimulation, then store-operated<br />
Ca entry may have an important role.<br />
VIII. COMMON OR SEPARATE CALCIUM POOLS<br />
A. Introduction<br />
Physiol Rev VOL 90 JANUARY 2010 www.prv.org<br />
The presence of two types (at least) of Ca release<br />
channels on the SR, which can <strong>in</strong>teract with each other<br />
to control local and global Ca signals, adds another<br />
level of complexity to the regulation of Ca signal<strong>in</strong>g by<br />
the SR <strong>in</strong> smooth muscles. The scope for such <strong>in</strong>teractions<br />
<strong>in</strong> any particular smooth muscle will depend on<br />
the morphological arrangement of the store(s), isoform<br />
expression, receptor distribution, and the cytoplasmic<br />
and lum<strong>in</strong>al [Ca] (Fig. 5). There is reasonable evidence<br />
to support the view that the SR has heterogeneous<br />
compartments of releasable Ca <strong>in</strong> smooth muscle cells.<br />
In view of this, it is helpful to frame the discussion that<br />
follows accord<strong>in</strong>g to the type of Ca store. These have<br />
been classified <strong>in</strong>to three subtypes: S (conta<strong>in</strong><strong>in</strong>g both<br />
IP 3 and RyRs), S (conta<strong>in</strong><strong>in</strong>g only IP 3 receptors) (281,<br />
285), and S (conta<strong>in</strong><strong>in</strong>g only RyRs) (307). The relative<br />
distribution of each of these stores can vary considerably,<br />
not only among different types of smooth muscles<br />
but also among different species and with development.<br />
In the studies described below, a couple of general<br />
po<strong>in</strong>ts should be borne <strong>in</strong> m<strong>in</strong>d. First, a variety of<br />
different agonists, appropriate to particular smooth<br />
muscles, have been used as a mechanism to generate<br />
IP 3, and any differences <strong>in</strong> their other actions are often<br />
ignored. Second, when conclusions are based on pharmacological<br />
data, the specificity or otherwise of the<br />
drugs must not be overlooked. Mention has already<br />
been made of the problems associated with this approach<br />
to IP 3 receptor blockade, and similar concerns<br />
over some agents used to <strong>in</strong>hibit RyRs have also been<br />
raised (433).<br />
B. One Store With One Type of Receptor<br />
One of the clearest examples of cells hav<strong>in</strong>g just one<br />
type of Ca release channel is provided by the ureter. In rat