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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154 SUSAN WRAY AND THEODOR BURDYGA<br />
to the SR release site (505, 555), and the plasma membrane<br />
is <strong>in</strong> close proximity; thus BK channels are activated<br />
despite their low aff<strong>in</strong>ity for Ca. A s<strong>in</strong>gle Ca spark<br />
can produce 20 mV hyperpolarization <strong>in</strong> an isolated<br />
myocyte through activation of BK channels (202, 507).<br />
Vascular myocytes have a relatively high density of BK<br />
channels and do not require cluster<strong>in</strong>g of BK channels<br />
above a spark site. However, <strong>in</strong> visceral smooth muscle<br />
cells, where the density of BK channels is low, cluster<strong>in</strong>g<br />
of BK channels <strong>in</strong> the patches of the plasma membrane at<br />
sites frequently discharg<strong>in</strong>g sparks is required (525, 809).<br />
C. SK and IK Channels<br />
There are four different isoforms of the SK channel,<br />
SK1-4 (480), with SK4 also known as IK1. The clon<strong>in</strong>g of<br />
SK channels revealed the existence of at least three members<br />
of a family (SK1-3) (362), which were first identified<br />
<strong>in</strong> cultured rat skeletal muscle (55). These channels are<br />
highly sensitive to Ca (EC 50 0.5–0.7 M) and have a<br />
small s<strong>in</strong>gle-channel conductance (4–14 pS). In addition,<br />
they are selectively blocked by the bee venom tox<strong>in</strong><br />
apam<strong>in</strong> (135, 190, 247, 250, 254, 256). Of the three cloned<br />
SK channel subtypes (SK1-3), SK1 and SK3 channels are<br />
least sensitive to apam<strong>in</strong> (nanomolar apam<strong>in</strong> was required<br />
for their <strong>in</strong>hibition), and SK2 channels were more<br />
sensitive and <strong>in</strong>hibited <strong>in</strong> the subnanomolar range (67,<br />
362, 626, 727).<br />
S<strong>in</strong>ce their <strong>in</strong>itial discovery, SK channels have been<br />
described <strong>in</strong> a number of cell types, <strong>in</strong>clud<strong>in</strong>g rat pituitary<br />
cells (381), T lymphocytes (227), and adrenal chromaff<strong>in</strong><br />
cells (543). They have also been identified <strong>in</strong> some types<br />
of smooth muscles, e.g., ur<strong>in</strong>ary bladder (698), stomach<br />
(673), colon (364), uterus (360, 450), renal artery (206),<br />
portal ve<strong>in</strong> (293), and the pancreatic arterioles (666).<br />
Their distribution and functional importance are currently<br />
be<strong>in</strong>g established (247, 248, 256, 663), but there is<br />
evidence that SK3 is particularly relevant to contractility<br />
and excitability <strong>in</strong> smooth muscle. <strong>Function</strong>al studies performed<br />
on the <strong>in</strong>tact bladder revealed SK channels contribute<br />
to the afterhyperpolarization (AHP) follow<strong>in</strong>g<br />
tra<strong>in</strong>s of action potentials (255), as apam<strong>in</strong> blocked the<br />
AHP and <strong>in</strong>creased excitability and contractility without<br />
affect<strong>in</strong>g other parameters of the action potential.<br />
There is evidence that both SR Ca release and plasmalemmal<br />
Ca entry can activate SK channels. Hererra and<br />
Nelson (256) reported that SK channels <strong>in</strong> the bladder are<br />
activated by the rise <strong>in</strong> [Ca] which occurs upon Ca entry<br />
through L-type Ca channels dur<strong>in</strong>g the action potential<br />
but not by Ca sparks (256). The <strong>in</strong>ability of Ca sparks to<br />
activate SK channels was expla<strong>in</strong>ed by the small density<br />
of the SK channels near the discharg<strong>in</strong>g sites. Indeed, the<br />
density of SK channels <strong>in</strong> bladder myocytes was estimated<br />
to be 200 times lower than that of BK or L-type<br />
Physiol Rev VOL 90 JANUARY 2010 www.prv.org<br />
Ca channels (257). The activation of SK channels occurs<br />
through the b<strong>in</strong>d<strong>in</strong>g of Ca to calmodul<strong>in</strong>, which is constitutively<br />
bound to the COOH term<strong>in</strong>us of the channel<br />
(503). Thus SK channels are well suited to respond to<br />
changes <strong>in</strong> global [Ca] (0.1–1 M), s<strong>in</strong>ce calmodul<strong>in</strong> is<br />
saturated by [Ca] below 1 M. However, Kong et al. (368)<br />
showed that IP 3-<strong>in</strong>duced Ca release <strong>in</strong> colonic myocytes<br />
activated SK. Their activation has been suggested to underlie<br />
the hyperpolarization and relaxation associated<br />
with <strong>in</strong>hibitory pur<strong>in</strong>ergic <strong>in</strong>put on these cells. The SK<br />
channels are also responsible for the hyperpolarization <strong>in</strong><br />
response to release of ATP from enteric <strong>in</strong>hibitory motorneurons<br />
(360). More studies are required before it is<br />
known if this is common to other smooth muscles.<br />
When mice were produced <strong>in</strong> which SK3 was absent,<br />
no aberrant phenotype was observed (68). However, overexpression<br />
of SK3 unexpectedly led to difficulties <strong>in</strong><br />
breath<strong>in</strong>g and parturition. Labor was prolonged and described<br />
as dystocic. These data suggest SK channel downregulation<br />
may be required for parturition and labor. Modzelewska<br />
et al. (485) subsequently showed that apam<strong>in</strong><br />
<strong>in</strong>hibits NO-<strong>in</strong>duced relaxation of the myometrium, but<br />
did not affect spontaneous contractions. In bladder, <strong>in</strong>hibition<br />
of SK3 channels has been associated with <strong>in</strong>stability<br />
(257).<br />
The IK channel, also known as KCNN4, K3.1, and<br />
formerly SK4 (527, 747), is the product of different genes<br />
from SK1-3 and exhibits only 40% am<strong>in</strong>o acid sequence<br />
identity (40). The IK have conductances of 50–70 pS<br />
(718). These channels are blocked by TRAM-34 and clotrimazole,<br />
are sensitive to charybdotox<strong>in</strong> but <strong>in</strong>sensitive<br />
to apam<strong>in</strong>, and are not time or voltage dependent (506). It<br />
is now considered that IK channels are the Gardos channels<br />
of erythrocytes, responsible for their high K permeability<br />
(269).<br />
In the endothelium, IK channels contribute to endothelial<br />
derived hyperpolariz<strong>in</strong>g factor (EDHF)-mediated<br />
responses. Deletion of IK channels attenuates ACh-<strong>in</strong>duced<br />
hyperpolarization of endothelial cells and vascular<br />
myocytes (637; see also Ref. 179). Blood pressure was<br />
elevated <strong>in</strong> the IK knockout mice <strong>in</strong> agreement with a role<br />
for EDHF <strong>in</strong> its regulation (81).<br />
The IK channel may be associated with proliferat<strong>in</strong>g<br />
arterial and airway smooth muscle (510, 628). The latter<br />
authors showed IK expression <strong>in</strong> human airway and suggest<br />
that their upregulation plays a role <strong>in</strong> disease. The<br />
mRNA for IK channels has also been found <strong>in</strong> human<br />
trachea (628). It is likely that IK channels will contribute<br />
to sett<strong>in</strong>g the membrane potential relatively negative <strong>in</strong><br />
the cells that express them. As mentioned already, IK<br />
channels <strong>in</strong> endothelial cells can lead to hyperpolarization<br />
of vascular myocytes. In human pulmonary artery, IK<br />
expression and current have been shown, but these are<br />
likely to come from endothelial cells not myoctyes (301,<br />
564). Thus, although there is a physiological importance