Sarcoplasmic Reticulum Function in Smooth Muscle - Physiological ...

140 SUSAN WRAY AND THEODOR BURDYGA
in the vascular preparation is due to increased SERCA
reserve compared with the heart or some form of compensatory
regulation of other parameters. When CPA is
used to inhibit SERCA in blood vessels, clear effects are
seen (504). When SERCA3-deficient mice were examined,
the relaxation to ACh was reduced in aorta (402) and to
substance P in trachea (334); however, as discussed earlier,
these effects are not direct on the myocytes, but
rather are due to endothelial- and epithelial-dependent
effects. No overt phenotype is associated with the
SERCA3 knockout (402). This appears to be the extent of
the literature on gene targeting studies of SERCA function
in smooth muscle. There is, however, a more extensive
literature concerning effects obtained with CPA and thapsigargin.
In most smooth muscles, a clear elevation of
baseline tension is found with SERCA inhibition, and
when measured, this can be seen to be accompanied by
increased global Ca signals [ileal (710), aorta (417, 629),
fundus (562), esophageal (640), uterus (377, 446, 682)].
Before the link between SR Ca release and BK
channels and membrane hyperpolarizations were elucidated,
many authors interpreted their data, i.e., SERCA
inhibition increases [Ca] and contraction, in terms of
the SR blocking or buffering the flow of Ca to the
myofilaments. The spark-STOC coupling mechanisms,
however, can directly account for the effect of SERCA
inhibition in many, but importantly, not all smooth
muscles. The effects of SERCA inhibition on Ca signaling
and contractility in phasic smooth muscles can be
very pronounced. For example, in the neonatal uterus
(519) or term myometrium (707), the normal phasic
activity becomes tonic-like.
D. SERCA Ca Efflux and Relaxation
Although SERCA takes up Ca and aids restoration of
[Ca] to resting levels following smooth muscle stimulation,
there is evidence from uterine smooth muscle to
show that acting on its own, it does not significantly alter
the decay of the Ca transient, but rather, it enhances
efflux mechanisms. In isolated uterine myocytes (631)
when PMCA and NCX were blocked, intracellular [Ca] did
not fall after stimulation (644). However, if SERCA was
blocked, but not PMCA and NCX, then the decay of the Ca
transient was slowed. This was the case whether Ca efflux
was via PMCA or NCX or both. We concluded that when
SERCA is active, it takes up a portion of Ca entering the
cell, and the SR then releases Ca in a directed manner
towards the plasma membrane extruders, thereby maximizing
their efficiency (see also Refs. 184, 445). A study in
airway myocytes also concluded that the decay of the Ca
transient was not altered by SERCA, although it is active
(603). These authors suggested that mitochondria take up
Ca and contribute to the decrease in [Ca]. In an earlier
study in isolated tracheal myocytes, SERCA had been
shown to contribute to the decay of agonist-induced Ca
transients as the decay was slower when SERCA was
inhibited (640).
E. Store-Operated Ca Entry
1. Introduction
Physiol Rev VOL 90 JANUARY 2010 www.prv.org
The Ca content of the SR acts as a powerful factor
controlling the open probabilities of both RyR and IP 3R
channels (see sects. IV and VII). Depletion of Ca stores in
smooth muscle cells by SERCA pump inhibitors results in
an inhibition of Ca sparks and STOCs in those tissues
producing them. This in turn can lead to depolarization of
the cell membrane and activation of Ca entry via L-type
Ca channels, as was reported for rat cerebral arteries
(507). However, in addition to activation of L-type Ca
channels, depletion of SR Ca can also activate nifedipineresistant
Ca entry, through opening of Ca release-activated
Ca channels (CRAC). In nonexcitable cells, ER Ca
depletion opens voltage-independent plasma membrane Ca
channels through which extracellular Ca enters the cell to
refill the store. These are termed “capacitative calcium entry”
(CCE) channels (542, 579, 580). The role of CCE, also
known as store-operated Ca entry (SOCE) and Ca entry
mechanism across the sarcolemma of the smooth muscles,
is still being determined.
Recent work has identified the specific molecular
components, Stim and Orai, which constitute the Ca sensor
in the ER/SR and the Ca channel, respectively, and
their discovery has helped to clarify the mechanisms of
CCE. The process and mechanisms of SOCE have been
best studied in nonexcitable cells, where the process was
first discovered, and studies in smooth muscle are relatively
sparse. Therefore, an overview of current knowledge
taken from the literature on nonexcitable cells will
be given to set the scene for smooth muscle.
2. Overview of store depletion, Orai, STIM1,
and TRPCs
This account is based on information in several recent
reviews that have appeared since the discovery of
Stim (stromal interaction molecule 1) proteins (99, 173,
189, 260, 524, 569, 581, 649).
Agonist binding to cell membranes and subsequent
generation of IP 3 leads not only to ER Ca release, but also
to activation of Ca channels in the plasma membrane.
This connected depletion and loading of the ER Ca store
was termed capacitative Ca entry by Putney in 1986 (578)
and is synonymous with the term store-operated Ca entry.
This form of Ca entry is the major route of Ca entry in
nonexcitable cells, which lack functional voltage-gated Ca
channels. It was subsequently demonstrated that the Ca