Sarcoplasmic Reticulum Function in Smooth Muscle - Physiological ...

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