Sarcoplasmic Reticulum Function in Smooth Muscle - Physiological ...

130 SUSAN WRAY AND THEODOR BURDYGA
bound to calreticulin (501), and if its expression is deficient,
then the ER Ca storage capacity is decreased and
agonist-evoked Ca release is inhibited (467, 501). Conversely,
overexpression leads to increased Ca storage
capacity and a decrease in store-operated Ca influx (466).
Emptying of the ER Ca store stimulates expression of
calreticulin (744). Thus changes in calreticulin concentration
may be expected to have a direct effect on Ca signaling,
as well as indirect ones, as its chaperone function
is also affected (470). Cardiac development is so impaired
in calreticulin knockout mice that they die at the embryonic
stage (467). However, in adult heart, the level of
calreticulin expression is low, and its overexpression produces
arrhythmias, heart block, and death (500).
G. Triadin and Junctin
While many proteins have been identified in the SR
lumen (51, 424), two that are abundant and intrinsic to the
SR membrane are triadin and junctin (38, 340). They
appear to anchor calsequestrin to the junctional face of
the SR membrane, perhaps to keep it close to Ca release
channels. The binding to calsequestrin is disrupted by low
(10 M) and high (10 mM) [Ca] (803). It is also possible
that these two proteins are SR luminal Ca sensors
and modulators of RyR open probability (51, 359, 803). To
date, triadin and junctin do not appear to have been
described in smooth muscle. This may be a consequence
of the lack of triad and diad arrangement of the SR in
smooth muscle, but it may also be due to lower expression
levels, methodological difficulties (443), or that different
isoforms occur. For example, recent data have
identified new triadin isoforms, which colocalize with
IP 3R (721). Thus there may be an IP 3R-specific complex
that could be in smooth muscle. Similarly triadin and
junction by mediating interactions with calsequestrin
could have function in smooth muscle if expressed there
(237).
H. Summary
In summary, while it is clear that for the SR to
function as a Ca store the Ca binding proteins calreticulin
and calsequestrin are required, little data are available
investigating the functional effects of altering their expression
in smooth muscle. Nor is it clear what advantages
or specificity is conferred on smooth muscles by
their expressing the different proteins or their isoforms.
Little recent data have been obtained in this field despite
the increased interest in how luminal Ca content affects
Ca signaling and functions in smooth muscle. Triadin and
junctin may not be expressed in smooth muscle, but
verification of this would be helpful. We concur with the
words of Volpe et al. (730) written more than a decade
ago on this issue that “it is therefore possible that what at
present appears to be no more than a complex pleiotropism
could ultimately be attributed to specific physiological
characteristics of the various smooth muscles.” We
have however come no closer to examining this possibility
in the intervening years.
V. CALCIUM RELEASE CHANNELS
A. Introduction
Ca release from the SR in smooth muscle cells occurs
though activation of two families of Ca release channels:
RyR and IP 3R channels, which have substantial similarities
in structure (113, 657). These channels are involved in
control of various functions in smooth muscle cells including
contraction, relaxation, proliferation, and differentiation
(31). The functional role of RyR and IP 3R channels
in these processes critically depends on molecular
identity, level and proportion of expression, subcellular
distribution, and the types of functional units they form
with other cellular structures. Smooth muscles differ by
types (vascular and visceral), location (different vascular
beds or various hollow organs), size (resistance versus
conduit arteries), orientation (circular versus longitudinal),
and function (phasic versus tonic), and it is not
surprising that the data obtained so far indicate marked
differences in expression, spatial distribution, and subcellular
location of different isoforms of RyRs and IP 3Rs and
that these underlie the generation of tissue- or cell-specific
Ca responses (224, 292, 493, 765, 794). NAADP is an
agonist at RyRs, but there may also be a third Ca release
channel, which is discussed in the section VD.
B. Ryanodine Receptors
Physiol Rev VOL 90 JANUARY 2010 www.prv.org
The RyR is a homotetramer with the (565 kDa)
subunits surrounding a central Ca pore. The subunits act
in a coordinated way to gate the Ca channel and are also
each associated with an important 12-kDa regulatory
binding protein FKBP (427, 461). Cryo-EM and threedimensional
reconstruction reveal that RyR is a symmetrical
mushroom like structure with a large cytosolic assembly
and a short region that traverses the SR membrane
(610, 624). The ion channel-forming, membranespanning
regions are highly conserved between different
RyR isoforms and are localized to the COOH terminus.
The cytosolic domain consists of 80% of the mass of the
RyRs. It assumes a quatrefoil shape and is the modulatory
region of the molecule, containing binding sites for Ca,
adenine nucleotides, calmodulin, FKBPs, as well as phosphorylation
sites (624). The massive size of RyRs makes
them physically the largest ion channels (almost twice as