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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142 SUSAN WRAY AND THEODOR BURDYGA<br />
to a depletion of SR Ca. Previous work had <strong>in</strong>vestigated<br />
TRPC channels as the putative Ca entry mechanism<br />
opened by store Ca depletion, but the grow<strong>in</strong>g consensus<br />
is that they are not responsible for I crac. Therefore, it may<br />
be argued that TRPCs are unlikely to be responsible for<br />
SOCE <strong>in</strong> smooth muscles. This has already been suggested<br />
by some (153, 722, 738) but contested by others<br />
(e.g., Ref. 7). TRPC1, the TRP most thought to be <strong>in</strong>volved<br />
<strong>in</strong> SOCE and highly expressed <strong>in</strong> smooth muscles, had no<br />
effect on vascular function or SOCE when knocked out<br />
(12). In TRPC6 knockout mice, enhanced DAG and agonist-<strong>in</strong>duced<br />
current <strong>in</strong> smooth muscle cells was reported,<br />
i.e., the opposite result expected if TRPC6 is <strong>in</strong>volved <strong>in</strong><br />
SOCE (188). RNA <strong>in</strong>terference (RNAi)-based high-throughput<br />
screens also revealed no effect on SOCE activation of<br />
TRP channel knockdown, <strong>in</strong> contrast to Stim (400). As<br />
with studies on nonexcitable cells, caution must be applied<br />
to studies where genes have been knocked out or<br />
overexpressed, and <strong>in</strong> smooth muscle, when cells have<br />
been cultured, the physiological relevance of such studies<br />
is even harder to <strong>in</strong>terpret (274). Nevertheless, while it is<br />
premature to rule TRPCs out of <strong>in</strong>volvement <strong>in</strong> SOCE <strong>in</strong><br />
smooth muscle cells, especially as much of the Orai work<br />
has been conducted on nonexcitable cells, it nevertheless<br />
does not appear profitable to cover <strong>in</strong> great depth previous<br />
studies related to a role <strong>in</strong> SOCE of TRPC, especially<br />
as this has recently been reviewed (7). A recent report by<br />
Dehaven et al. (148) demonstrated that TRPC functions<br />
<strong>in</strong>dependently of Orai1 <strong>in</strong> vascular myocytes (A7r5 and<br />
A10 cell l<strong>in</strong>es) and suggests that TRPCs are activated by<br />
PLC and do not <strong>in</strong>volve Stim1 as the Ca sensor and TRCPs<br />
open nonselective cation channels when stimulated by<br />
arg<strong>in</strong><strong>in</strong>e vasopress<strong>in</strong>. Roles for TRCPs other than <strong>in</strong> storeoperated<br />
Ca entry <strong>in</strong> smooth muscle have been well demonstrated<br />
for receptor-operated channels, where they<br />
constitute nonspecific cation channels (39, 457) and<br />
stretch channels (658), but these are outside the scope of<br />
this review.<br />
There is already evidence to support the Stim-Orai<br />
model for SOCE <strong>in</strong> some smooth muscles: airway, Stim-1<br />
(549), Orai (550); vascular, Stim (153, 413, 685), Stim and<br />
Orai (47, 210); and uterus, Stim and Orai (611). The list of<br />
smooth muscles express<strong>in</strong>g Stim and Orai is expected to<br />
grow rapidly as more studies are performed. To date<br />
however, there is already evidence that capacitative Ca<br />
entry/SOCE <strong>in</strong> some smooth muscles at least occurs via<br />
the Stim-Orai mechanism. Dietrich et al. (153) <strong>in</strong>hibited<br />
SOCE us<strong>in</strong>g siRNA aga<strong>in</strong>st Stim1, whereas TRCP1 knockout<br />
did not affect it. Further support for a physiological<br />
function for these prote<strong>in</strong>s <strong>in</strong> smooth muscles comes<br />
from data show<strong>in</strong>g that their expression levels are altered<br />
at different sites and <strong>in</strong> disease. Thus Orai and Stim were<br />
upregulated <strong>in</strong> proliferat<strong>in</strong>g arterial myocytes, lead<strong>in</strong>g the<br />
authors to suggest that they play a critical role <strong>in</strong> the<br />
altered Ca handl<strong>in</strong>g that occurs dur<strong>in</strong>g vascular growth<br />
Physiol Rev VOL 90 JANUARY 2010 www.prv.org<br />
and remodel<strong>in</strong>g (47). Stim1 expression was greater <strong>in</strong> the<br />
distal than proximal part of the pulmonary artery, where<br />
SOCE is also greatest (413). Stim1 and Orai1 were also<br />
found to be upregulated <strong>in</strong> aortas from hypertensive rats<br />
(210). Knockdown of Orai1 reduced thapsigarg<strong>in</strong>-<strong>in</strong>duced<br />
Ca <strong>in</strong>flux and reduced I crac (210).<br />
Thus, <strong>in</strong> summary, Orai and Stim appear to constitute<br />
the molecular mechanism underly<strong>in</strong>g capacitative Ca entry<br />
and I crac <strong>in</strong> nonexcitable cells, and there is mount<strong>in</strong>g<br />
evidence for this also to be the case <strong>in</strong> smooth muscle. To<br />
us, the most urgent questions revolve around whether<br />
there is only one form of SOCE <strong>in</strong> smooth muscle and if<br />
this <strong>in</strong>volves only the Stim-Orai mechanism. The relative<br />
simplicity of Ca entry <strong>in</strong> nonexcitable cells falls away <strong>in</strong><br />
studies of smooth muscle, as SOCE is a variable feature<br />
between myocytes, and several other Ca entry pathways<br />
exist. In addition, there are only relatively few studies that<br />
have gone beyond demonstrat<strong>in</strong>g a putative SOCE, i.e.,<br />
mechanistic details, measurement of I crac, and biophysical<br />
and imag<strong>in</strong>g studies are sparse, lead<strong>in</strong>g to <strong>in</strong>terpretation<br />
based on only a few myocyte preparations. The <strong>in</strong>teraction<br />
of TRPCs and Orai channels, if any, also requires<br />
resolution.<br />
4. Evidence for store-operated Ca entry<br />
<strong>in</strong> smooth muscle<br />
As one might anticipate from know<strong>in</strong>g that the contribution<br />
of voltage-gated Ca entry varies between smooth<br />
muscles, be<strong>in</strong>g high for example <strong>in</strong> uter<strong>in</strong>e (771) and<br />
<strong>in</strong>test<strong>in</strong>al (64) and low <strong>in</strong> many large blood vessels and<br />
tracheal myocytes (7), so the contribution of Ca entry<br />
through SOCE and/or other voltage-<strong>in</strong>dependent routes<br />
such as nonspecific receptor-operated cation channels<br />
(ROCs) shows considerable variation between smooth<br />
muscles (44). Although ROC activity is a feature of agonist<br />
b<strong>in</strong>d<strong>in</strong>g, e.g., norep<strong>in</strong>ephr<strong>in</strong>e, and is important for<br />
their physiological effects (39), it does not <strong>in</strong>volve SR Ca<br />
depletion, and therefore, these channels are not discussed<br />
<strong>in</strong> detail further.<br />
In smooth muscles, SOCE has been associated with a<br />
second, delayed Ca response to agonist applications; the<br />
IP 3 formed causes an <strong>in</strong>itial fast and transient release of<br />
Ca from the SR, followed by the slower process of SOCE<br />
which produces a more or less susta<strong>in</strong>ed Ca signal, often<br />
of lower amplitude than the <strong>in</strong>itial transient rise. If Ca<br />
sensitization mechanisms are also stimulated by the agonist,<br />
then the force responses will not be directly related<br />
to the Ca signal and force may cont<strong>in</strong>ue long after [Ca]<br />
has fallen.<br />
A susta<strong>in</strong>ed <strong>in</strong>crease <strong>in</strong> [Ca] due to extracellular Ca<br />
entry follow<strong>in</strong>g agonist application has been taken as<br />
evidence for SOCE by many <strong>in</strong>vestigators, sometimes augmented<br />
by data from putative blockers of SOCE such as<br />
SKF96365 and La 3 . It is generally accepted that there are