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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152 SUSAN WRAY AND THEODOR BURDYGA<br />
utor to the global Ca signal is still a matter for future<br />
experiments. That <strong>in</strong>hibition of SR function by SERCA<br />
<strong>in</strong>hibitors results <strong>in</strong> 70% <strong>in</strong>hibition of the [Ca] rises <strong>in</strong><br />
the area of discharge sites <strong>in</strong> ur<strong>in</strong>ary bladder and vas<br />
deferens strongly suggests that CICR is present <strong>in</strong> these<br />
tissues and can produce a significant contribution to the<br />
cytoplasmic [Ca] rise. However, as under the same conditions,<br />
that global rises of [Ca] were not <strong>in</strong>hibited, but <strong>in</strong><br />
fact were slightly potentiated, as also reported for a number<br />
of <strong>in</strong>tact phasic smooth muscles, suggests that CICR<br />
is conf<strong>in</strong>ed to microdoma<strong>in</strong>s. Studies us<strong>in</strong>g other types of<br />
smooth muscles and different species should be carried<br />
out. High temporal and spatial resolution and analyses of<br />
the Ca release from the SR should be correlated with the<br />
isoform expression and spatial distribution of different<br />
types of RyRs.<br />
6. Ca sparks and myogenic tone<br />
Many resistance arteries possess an <strong>in</strong>tr<strong>in</strong>sic “myogenic”<br />
tone, activated <strong>in</strong> response to elevation of <strong>in</strong>travascular<br />
pressure by a graded membrane depolarization,<br />
open<strong>in</strong>g Ca channels, and lead<strong>in</strong>g to elevation <strong>in</strong> [Ca] and<br />
constriction (507). It has been proposed that Ca sparks,<br />
by target<strong>in</strong>g BK channels, generate STOCs, which cause a<br />
tonic hyperpolariz<strong>in</strong>g <strong>in</strong>fluence on the membrane potential<br />
of small pressurized arteries with myogenic tone<br />
(507). Inhibition of Ca sparks or BK channels causes<br />
membrane depolarization, lead<strong>in</strong>g to further elevation of<br />
[Ca], and additional <strong>in</strong>creases <strong>in</strong> muscle tone <strong>in</strong> pressurized<br />
cerebral arteries (330, 356, 507). Thus, <strong>in</strong> resistance<br />
arteries, a Ca sparks/STOCs coupl<strong>in</strong>g mechanism can act<br />
as a negative-feedback mechanism to oppose myogenic<br />
Ca entry via Ca channels and promote relaxation (507).<br />
However, under voltage-clamp conditions, global rises of<br />
[Ca] <strong>in</strong>duced by depolariz<strong>in</strong>g voltage step <strong>in</strong> myocytes<br />
isolated from these arteries were significantly <strong>in</strong>hibited by<br />
ryanod<strong>in</strong>e. This suggested that CICR is also present <strong>in</strong><br />
these cells and can act as an amplify<strong>in</strong>g mechanism (507).<br />
However, under normal physiological conditions, this<br />
mechanism may contribute little, as block<strong>in</strong>g Ca sparks <strong>in</strong><br />
the presence of blockers of BK channels has little effect<br />
on global [Ca] and arterial tone (330). Myogenic tone is<br />
associated with moderate depolarization (356, 357, 507),<br />
and it was suggested that L-type Ca channels operate <strong>in</strong> a<br />
“low-activity mode,” i.e., the myocytes never depolarize<br />
sufficiently to achieve a high channel P o.<br />
We conclude that the Ca sparks/STOCs coupl<strong>in</strong>g<br />
mechanism acts as a powerful vasodilator <strong>in</strong> vascular<br />
beds where membrane potential depolarization acts as an<br />
activat<strong>in</strong>g mechanism to generate tone. If muscle tone is<br />
activated via stimulation of Ca entry by SOC or ROC<br />
channels, this mechanism will be <strong>in</strong>effective, as it will be<br />
<strong>in</strong> controll<strong>in</strong>g tone produced by the Ca oscillations associated<br />
with activation of IP 3Rs. However, this mechanism<br />
can play an important role <strong>in</strong> disabl<strong>in</strong>g the mechanisms of<br />
generation of the action potential, which is a feature of<br />
most of the arteriolar smooth muscle cells and enables<br />
them to be regulated by local factors.<br />
B. Ca Puffs<br />
Physiol Rev VOL 90 JANUARY 2010 www.prv.org<br />
The term Ca puffs refers to the small local <strong>in</strong>creases<br />
<strong>in</strong> [Ca] that occur when IP 3Rs open spontaneously or <strong>in</strong><br />
response to agonists. Unlike sparks, Ca puffs have not<br />
been detected <strong>in</strong> vascular myocytes despite the obvious<br />
presence of IP 3Rs. So far, Ca puffs have been detected <strong>in</strong><br />
only two smooth muscles: rat ureter (60) <strong>in</strong> which agonist-<strong>in</strong>duced<br />
Ca release plays a dom<strong>in</strong>ant role <strong>in</strong> modulat<strong>in</strong>g<br />
contraction (34, 86) and mur<strong>in</strong>e colonic myocytes. In<br />
rat ureteric myocytes, Ca puffs were observed dur<strong>in</strong>g<br />
release of low concentrations of IP 3 from a caged precursor,<br />
or by low concentrations of ACh. They were also<br />
observed spontaneously <strong>in</strong> Ca-overloaded myocytes (91).<br />
Spontaneous Ca puffs were observed <strong>in</strong> <strong>in</strong>tact rat ureteric<br />
preparations (60).<br />
Calcium puffs <strong>in</strong> tissues appear to have a wide<br />
range of amplitudes, time courses, and spatial spread,<br />
suggest<strong>in</strong>g that the IP 3Rs exist <strong>in</strong> clusters of variable<br />
numbers of channels and that with<strong>in</strong> these clusters a<br />
variable number of channels can be recruited (86).<br />
Calcium puffs <strong>in</strong> the ureteric myocytes were blocked<br />
selectively by <strong>in</strong>tracellular applications of hepar<strong>in</strong> and<br />
an antibody to IP 3R, but were unaffected by ryanod<strong>in</strong>e<br />
and <strong>in</strong>tracellular application of an antibody to RyR (60).<br />
When stimulated by agonists, propagated, ryanod<strong>in</strong>eresistant<br />
Ca waves appeared to result from the spatial<br />
recruitment of Ca-release sites by diffusion. This is<br />
consistent with data from multicellular preparations,<br />
where ryanod<strong>in</strong>e-resistant agonist-<strong>in</strong>duced Ca release<br />
was reported (34). Both Ca signals provide an <strong>in</strong>tegrated<br />
mechanism to regulate contractility <strong>in</strong> smooth<br />
muscle cells, where RyRs are absent, or poorly expressed.<br />
The possible role of Ca puffs <strong>in</strong> the control of excitability of<br />
rat ureteric smooth muscle cells has not been <strong>in</strong>vestigated,<br />
although we have observed spontaneous transient outward/<br />
<strong>in</strong>ward currents (STOICs) (Burdyga and Wray, unpublished<br />
data), which could result from activation of the BK and Cl Ca<br />
channels (91, 92).<br />
Localized Ca transients and puffs, resistant to ryanod<strong>in</strong>e<br />
and <strong>in</strong>hibited by xestospong<strong>in</strong>, U-73122 (an <strong>in</strong>hibitor<br />
of PLC), occurred spontaneously or dur<strong>in</strong>g P2Y receptor<br />
stimulation <strong>in</strong> mur<strong>in</strong>e colonic myocytes (34). The<br />
puffs were coupled to the activation of both BK and<br />
small-conductance Ca-activated K (SK) channels. Thus<br />
the release of Ca by G prote<strong>in</strong>-mediated activation of PLC<br />
can be l<strong>in</strong>ked to <strong>in</strong>hibitory responses via Ca puffs target<strong>in</strong>g<br />
SK channels. This is <strong>in</strong> marked contrast to the usual<br />
f<strong>in</strong>d<strong>in</strong>g that IP 3-dependent mechanisms are used by excitatory<br />
agonists <strong>in</strong> smooth muscles.