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