Sarcoplasmic Reticulum Function in Smooth Muscle - Physiological ...

152 SUSAN WRAY AND THEODOR BURDYGA
utor to the global Ca signal is still a matter for future
experiments. That inhibition of SR function by SERCA
inhibitors results in 70% inhibition of the [Ca] rises in
the area of discharge sites in urinary bladder and vas
deferens strongly suggests that CICR is present in these
tissues and can produce a significant contribution to the
cytoplasmic [Ca] rise. However, as under the same conditions,
that global rises of [Ca] were not inhibited, but in
fact were slightly potentiated, as also reported for a number
of intact phasic smooth muscles, suggests that CICR
is confined to microdomains. Studies using other types of
smooth muscles and different species should be carried
out. High temporal and spatial resolution and analyses of
the Ca release from the SR should be correlated with the
isoform expression and spatial distribution of different
types of RyRs.
6. Ca sparks and myogenic tone
Many resistance arteries possess an intrinsic “myogenic”
tone, activated in response to elevation of intravascular
pressure by a graded membrane depolarization,
opening Ca channels, and leading to elevation in [Ca] and
constriction (507). It has been proposed that Ca sparks,
by targeting BK channels, generate STOCs, which cause a
tonic hyperpolarizing influence on the membrane potential
of small pressurized arteries with myogenic tone
(507). Inhibition of Ca sparks or BK channels causes
membrane depolarization, leading to further elevation of
[Ca], and additional increases in muscle tone in pressurized
cerebral arteries (330, 356, 507). Thus, in resistance
arteries, a Ca sparks/STOCs coupling mechanism can act
as a negative-feedback mechanism to oppose myogenic
Ca entry via Ca channels and promote relaxation (507).
However, under voltage-clamp conditions, global rises of
[Ca] induced by depolarizing voltage step in myocytes
isolated from these arteries were significantly inhibited by
ryanodine. This suggested that CICR is also present in
these cells and can act as an amplifying mechanism (507).
However, under normal physiological conditions, this
mechanism may contribute little, as blocking Ca sparks in
the presence of blockers of BK channels has little effect
on global [Ca] and arterial tone (330). Myogenic tone is
associated with moderate depolarization (356, 357, 507),
and it was suggested that L-type Ca channels operate in a
“low-activity mode,” i.e., the myocytes never depolarize
sufficiently to achieve a high channel P o.
We conclude that the Ca sparks/STOCs coupling
mechanism acts as a powerful vasodilator in vascular
beds where membrane potential depolarization acts as an
activating mechanism to generate tone. If muscle tone is
activated via stimulation of Ca entry by SOC or ROC
channels, this mechanism will be ineffective, as it will be
in controlling tone produced by the Ca oscillations associated
with activation of IP 3Rs. However, this mechanism
can play an important role in disabling the mechanisms of
generation of the action potential, which is a feature of
most of the arteriolar smooth muscle cells and enables
them to be regulated by local factors.
B. Ca Puffs
Physiol Rev VOL 90 JANUARY 2010 www.prv.org
The term Ca puffs refers to the small local increases
in [Ca] that occur when IP 3Rs open spontaneously or in
response to agonists. Unlike sparks, Ca puffs have not
been detected in vascular myocytes despite the obvious
presence of IP 3Rs. So far, Ca puffs have been detected in
only two smooth muscles: rat ureter (60) in which agonist-induced
Ca release plays a dominant role in modulating
contraction (34, 86) and murine colonic myocytes. In
rat ureteric myocytes, Ca puffs were observed during
release of low concentrations of IP 3 from a caged precursor,
or by low concentrations of ACh. They were also
observed spontaneously in Ca-overloaded myocytes (91).
Spontaneous Ca puffs were observed in intact rat ureteric
preparations (60).
Calcium puffs in tissues appear to have a wide
range of amplitudes, time courses, and spatial spread,
suggesting that the IP 3Rs exist in clusters of variable
numbers of channels and that within these clusters a
variable number of channels can be recruited (86).
Calcium puffs in the ureteric myocytes were blocked
selectively by intracellular applications of heparin and
an antibody to IP 3R, but were unaffected by ryanodine
and intracellular application of an antibody to RyR (60).
When stimulated by agonists, propagated, ryanodineresistant
Ca waves appeared to result from the spatial
recruitment of Ca-release sites by diffusion. This is
consistent with data from multicellular preparations,
where ryanodine-resistant agonist-induced Ca release
was reported (34). Both Ca signals provide an integrated
mechanism to regulate contractility in smooth
muscle cells, where RyRs are absent, or poorly expressed.
The possible role of Ca puffs in the control of excitability of
rat ureteric smooth muscle cells has not been investigated,
although we have observed spontaneous transient outward/
inward currents (STOICs) (Burdyga and Wray, unpublished
data), which could result from activation of the BK and Cl Ca
channels (91, 92).
Localized Ca transients and puffs, resistant to ryanodine
and inhibited by xestospongin, U-73122 (an inhibitor
of PLC), occurred spontaneously or during P2Y receptor
stimulation in murine colonic myocytes (34). The
puffs were coupled to the activation of both BK and
small-conductance Ca-activated K (SK) channels. Thus
the release of Ca by G protein-mediated activation of PLC
can be linked to inhibitory responses via Ca puffs targeting
SK channels. This is in marked contrast to the usual
finding that IP 3-dependent mechanisms are used by excitatory
agonists in smooth muscles.