Sarcoplasmic Reticulum Function in Smooth Muscle - Physiological ...

156 SUSAN WRAY AND THEODOR BURDYGA
of Ca spark discharge will be to trigger STICs (810), since
at these potentials the electrochemical driving force for Cl
will be greater than that for K. The discharge of STICs will
cause membrane depolarization and thus serve as a positive-feedback
mechanism to trigger the activation of voltage-gated
Ca channels and excitation of the myocytes. As
depolarization increases the frequency of Ca sparks and
STOCs, sensitivity of BK channels to Ca and the electrochemical
driving force for K will also be increased. This
will make BK more active and result in the generation of
high-amplitude STOCs and hyperpolarization. This would
lead to closure of voltage-gated Ca channels and relaxation
of smooth muscle, as was reported for pressurized
cerebral arteries (507). High sensitivity of Cl Ca to [Ca] and
low sensitivity to voltage make them ideal ion channels to
be targeted by agonists to elicit excitatory effects on
smooth muscle cells. Unlike STICs, the whole cell Cl Ca
currents decay much faster than global Ca transients as
the inactivation of Cl Ca current is determined not by
intracellular [Ca], but by phosphorylation of the channel
by CAM kinase II (739). Therefore, the decay of a STIC
appears to be determined by the decline of Ca sparks,
whereas the decay of the whole cell Cl Ca currents is
controlled by CAM kinase II activity.
To summarize these data, we conclude that the expression
of a range of different ion channels enables
muscles to perform diverse functions in the human body.
Recent data clearly indicate a role of the SR in the Ca
signaling that controls smooth muscle function, via coupling
Ca release from the SR to activation of ion channels.
Discovery of Ca sparks, waves, and oscillations that can
target several Ca-regulated channels (BK, SK, and IK) can
produce positive or negative feedback controlling contractility.
For example, some tonic contractions, which
can be achieved via sustained membrane depolarization
or discharge of bursts of action potentials, can be effectively
decreased via activation of a Ca sparks/STOCs coupling
mechanism. BK channels coupled to Ca sparks may
produce long refractory periods, whereas SK channels
targeted by Ca entry may be associated with short refractory
periods, as discussed above. Still other mechanisms
may be present in different smooth muscles, and a better
understanding of them would aid understanding of the
control of their contractility under normal and pathological
conditions.
XI. SARCOPLASMIC RETICULUM AND
DEVELOPMENT AND AGING
In the nervous system and heart there is a relatively
large amount of literature on the role of Ca homeostasis
and the SR, and a growing understanding of their importance
to aging, development, and pathology. Less is
known for smooth muscle, but there are some data spe-
cific to fetal and/or neonatal smooth muscles and aging
tissues and their SR, and this will be briefly presented.
Perhaps given the diversity of expression in Ca release
channels between different adult smooth muscles, it
should not be expected that a uniform thesis can be
presented. As some papers have examined both development
and aging, these data will be discussed together as
appropriate. As changes in [Ca] are considered to be
important for gene expression and pathological conditions
in very many tissues, their role in development and
aging in smooth muscles would seem to be worthy of
study. It should also be acknowledged that changes
involving the SR may be direct, e.g., SERCA expression,
or indirect, e.g., due to changes in Ca buffering or to
protein-coupled receptor sensitivity and IP 3 production.
Other changes with development, e.g., development
of force (502, 613), or Ca sensitivity (682), are not
considered here.
Although a complete data set is not available for any
smooth muscle, it would seem reasonable to conclude
that a change in the role of the SR occurs with the
transition from fetal and neonatal life to adulthood. There
is evidence for this at both structural and biochemical
levels, as well as from physiological studies. Care has to
be taken in the interpretation of these data as it is not
always possible to distinguish SR from ER, and thus to
establish if the greater ER protein production in the neonates
contributes to these differences. In addition, not all
studies have been able to report directly on either
intracellular or luminal [Ca]. Consequently, although
changes in SR Ca uptake and release and Ca pool size
can explain the data, effects on processes such as Ca
sensitization or excitability cannot always be excluded.
Nevertheless, a greater contribution of SR to smooth
muscle function in the neonate has been identified in a
number of instances, including uterus, bladder, and
some blood vessels.
Following examples in other tissues, where aging has
been linked to dysfunctions in Ca homeostasis and the SR
(409, 570, 616), studies in smooth muscles have also
pointed to alterations in Ca signaling (448, 593, 779). From
this review of the data, it is apparent that cytoplasmic
[Ca] can rise with aging in smooth muscles. This in turn
may be attributed to a decline in SERCA activity, although
more studies on this point are required. This rise in resting
[Ca] will produce overcontraction and contribute to
dysfunctions associated with aging such as hypertension
and incontinence urge.
XII. GENDER
Physiol Rev VOL 90 JANUARY 2010 www.prv.org
The effects of female hormones on the vasculature
and other smooth muscles are well recognized. While a
discussion of these interesting differences is beyond the