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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150 SUSAN WRAY AND THEODOR BURDYGA<br />
action potential, and both are <strong>in</strong>hibited by L-type Ca<br />
channel blockers, <strong>in</strong>dicat<strong>in</strong>g that Ca <strong>in</strong>flux is a key factor<br />
<strong>in</strong> the generation of the global Ca transients. Is CICR<br />
contribut<strong>in</strong>g to the global Ca transients associated with<br />
the action potential <strong>in</strong> smooth muscles?<br />
In the gu<strong>in</strong>ea pig ileum where Ca sparks have been<br />
observed (220), ryanod<strong>in</strong>e and thapsigarg<strong>in</strong> produced<br />
stimulant rather than <strong>in</strong>hibitory effects on the Ca transients<br />
associated with the action potential by <strong>in</strong>creas<strong>in</strong>g<br />
the amplitude and duration of the spike (203, 288, 312,<br />
494). Voltage-clamp experiments performed on ileum<br />
(361), cerebral arteries (330), portal ve<strong>in</strong> (133), vas deferens<br />
and bladder (288), and pregnant myometrium (630)<br />
demonstrated that Ca entry via L-type Ca channels can<br />
trigger some Ca release via RyRs. At the same time, other<br />
workers have failed to detect CICR <strong>in</strong> voltage-clamped<br />
smooth muscle cells isolated from other or even the same<br />
type of smooth muscles. For example, CICR was not<br />
detected <strong>in</strong> voltage-clamped smooth muscle cells of portal<br />
ve<strong>in</strong> (329), gastro<strong>in</strong>test<strong>in</strong>al tract (79, 781), and airways<br />
(178).<br />
A discussion of the physiological role of CICR <strong>in</strong><br />
ur<strong>in</strong>ary bladder smooth muscle cells illustrates the complexity<br />
<strong>in</strong> this area and the data which are hard to unify.<br />
Elegant work performed on voltage-clamped gu<strong>in</strong>ea pig<br />
ur<strong>in</strong>ary bladder myocytes by Ganitkevich and Isenberg<br />
(203) showed that Ca transients <strong>in</strong>duced by long depolariz<strong>in</strong>g<br />
voltage steps were <strong>in</strong>hibited 70% by ryanod<strong>in</strong>e.<br />
This suggested that a relatively high ga<strong>in</strong> “cardiac type” of<br />
CICR operates <strong>in</strong> these myocytes, at least under these<br />
experimental conditions. The importance of a functional<br />
contribution of CICR to E-C coupl<strong>in</strong>g and contraction <strong>in</strong><br />
ur<strong>in</strong>ary bladder smooth muscles has been assessed by<br />
several research groups, us<strong>in</strong>g different species and experimental<br />
models (127, 247, 254, 490, 494, 525). Results<br />
from these studies address<strong>in</strong>g the susceptibility to contraction<br />
<strong>in</strong> bladder myocytes treated with ryanod<strong>in</strong>e are<br />
not <strong>in</strong> agreement. For example, Hashitani and Brad<strong>in</strong>g<br />
(247) showed the <strong>in</strong>tracellular [Ca] rise <strong>in</strong>duced by spontaneous<br />
action potentials <strong>in</strong> the gu<strong>in</strong>ea pig was reduced to<br />
60% by ryanod<strong>in</strong>e. In a later publication (494), the stimulant<br />
action of ryanod<strong>in</strong>e on the mechanical activity of the<br />
gu<strong>in</strong>ea pig bladder was reported. Reduction of spontaneous<br />
or electrically evoked contractions by ryanod<strong>in</strong>e have<br />
been reported for mouse bladder myocytes (494). However,<br />
ryanod<strong>in</strong>e has no significant effect on the [Ca] and<br />
spontaneous contractions <strong>in</strong> rat bladder myocytes (252).<br />
These data suggest that the contribution of RyRs and<br />
CICR to E-C coupl<strong>in</strong>g <strong>in</strong> the bladder differs between<br />
species and experimental conditions.<br />
Imaizumi et al. (288) <strong>in</strong> gu<strong>in</strong>ea pig ur<strong>in</strong>ary bladder<br />
myocytes us<strong>in</strong>g brief (50 ms) depolariz<strong>in</strong>g voltage steps,<br />
obta<strong>in</strong>ed the first direct evidence that Ca “hot spots”<br />
(equivalent to Ca sparks) could be transiently activated <strong>in</strong><br />
cells depolarized to 20 mV. These events lasted for 0.5<br />
s and spread as Ca waves when depolarization was to 0<br />
mV. The <strong>in</strong>crease <strong>in</strong> global [Ca] elicited by 50 ms depolarization<br />
to 0 mV reached a peak 60–100 ms after the<br />
start of depolarization, <strong>in</strong>dicat<strong>in</strong>g that the spread of Ca<br />
hot spots cont<strong>in</strong>ued even after most voltage-dependent<br />
Ca channels had closed. Recently, Kotlikoff and co-workers<br />
(127) have also <strong>in</strong>vestigated the temporal relationship<br />
between the Ca current and local and global Ca signal<strong>in</strong>g<br />
<strong>in</strong> rabbit ur<strong>in</strong>ary bladder myocytes, under voltage- and<br />
current-clamp conditions with physiologically relevant<br />
protocols of stimulation. Localized photolysis of caged Ca<br />
<strong>in</strong>itiated CICR, but multiple excitation pulses were<br />
needed and IP 3R channels were also activated (313). Calcium<br />
channels were shown to activate RyRs to produce<br />
CICR <strong>in</strong> the form of Ca sparks and propagated Ca waves.<br />
Both the <strong>in</strong>itial Ca spark and the subsequent Ca waves<br />
occurred through the open<strong>in</strong>g of RyRs, s<strong>in</strong>ce both were<br />
elim<strong>in</strong>ated by ryanod<strong>in</strong>e, and neither was affected by<br />
dialysis with hepar<strong>in</strong> (127). They concluded that 1) L-type<br />
Ca channels could open without trigger<strong>in</strong>g Ca sparks,<br />
2) triggered Ca sparks could be observed after channel<br />
closure, 3) the trigger stimulus for the Ca release process<br />
is not a local but a global rise <strong>in</strong> <strong>in</strong>tracellular [Ca], and<br />
4) this results <strong>in</strong> a functional uncoupl<strong>in</strong>g of a s<strong>in</strong>gle action<br />
potential from Ca release.<br />
5. Loose coupl<strong>in</strong>g<br />
Physiol Rev VOL 90 JANUARY 2010 www.prv.org<br />
The small number of Ca spark sites evoked by the Ca<br />
current, the delay between Ca channel and RyR channel<br />
open<strong>in</strong>gs, as well as the <strong>in</strong>hibitory effect of BAPTA on Ca<br />
sparks <strong>in</strong> ur<strong>in</strong>ary bladder smooth muscle cells suggested<br />
that compared with cardiac myocytes, a fundamentally<br />
different coupl<strong>in</strong>g process operates <strong>in</strong> smooth muscle,<br />
which was termed “loose coupl<strong>in</strong>g” (127, 368). Features of<br />
the loose coupl<strong>in</strong>g system are low ga<strong>in</strong> (multiple Ca channels<br />
must open to produce sparks), discrim<strong>in</strong>ated responses<br />
(release takes the form of local Ca sparks or<br />
globally propagated Ca waves), and a marked lengthen<strong>in</strong>g<br />
of signal duration (Ca waves last far longer than the<br />
action potential). The delayed activation of CICR and the<br />
subsequent propagation of a Ca wave, which could last up<br />
to 1 s, suggests that CICR <strong>in</strong> contrast to cardiac muscle<br />
(122, 127) cannot be controlled by a brief (40–60 ms)<br />
s<strong>in</strong>gle action potential, and its functional role is yet to be<br />
established (368). Thus, <strong>in</strong> ur<strong>in</strong>ary bladder myocytes paradoxically,<br />
global rises of [Ca] are required to activate Ca<br />
sparks. The concept of loose coupl<strong>in</strong>g can also be expla<strong>in</strong>ed<br />
by an <strong>in</strong>crease <strong>in</strong> the SR [Ca] and activation of<br />
[Ca] sparks. An <strong>in</strong>crease <strong>in</strong> the lum<strong>in</strong>al [Ca] produces<br />
profound effects on both the frequency and the amplitude<br />
of Ca sparks <strong>in</strong> smooth muscle (811).<br />
Both cytosolic and SR Ca levels would be expected to<br />
<strong>in</strong>crease with enhanced Ca entry. The proximity of the SR<br />
to the plasma membrane and the existence of the uptake