Sarcoplasmic Reticulum Function in Smooth Muscle - Physiological ...

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