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