Whole cell current and membrane potential regulation by a
human smooth muscle mechanosensitive calcium channel
Adrian N.
Holm1,2,
Adam
Rich1,2,
Michael G.
Sarr3, and
Gianrico
Farrugia1,2
2 Division of Gastroenterology and Hepatology, Departments
of 1 Physiology and Biophysics and 3 Surgery, Mayo
Clinic, Rochester, Minnesota 55905
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ABSTRACT |
Mechanotransduction is
required for a wide variety of biological functions. The aim of this
study was to determine the effect of activation of a mechanosensitive
Ca2+ channel, present in human jejunal circular smooth
muscle cells, on whole cell currents and on membrane potential.
Currents were recorded using patch-clamp techniques, and perfusion of
the bath (10 ml/min, 30 s) was used to mechanoactivate the L-type
Ca2+ channel. Perfusion resulted in activation of L-type
Ca2+ channels and an increase in outward current from
664 ± 57 to 773 ± 72 pA at +60 mV. Membrane potential
hyperpolarized from
42 ± 4 to
50 ± 5 mV. In the
presence of nifedipine (10 µM), there was no increase in outward
current or change in membrane potential with perfusion. In the presence
of charybdotoxin or iberiotoxin, perfusion of the bath did not increase
outward current or change membrane potential. A model is proposed in
which mechanoactivation of an L-type Ca2+ channel current
in human jejunal circular smooth muscle cells results in increased
Ca2+ entry and cell contraction. Ca2+ entry
activates large-conductance Ca2+-activated K+
channels, resulting in membrane hyperpolarization and relaxation.
small intestine; patch clamp; stretch activation
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INTRODUCTION |
MECHANOTRANSDUCTION IS
REQUIRED for a variety of biological functions, such as touching,
hearing, balance, regulation of blood flow, cardiovascular function,
regulation of hollow organ volume, and regulation of bone and muscle
growth (6, 12-13). The unitary element that underlies
mechanotransduction is the ion channel. Mechanosensitive ion channels,
also known as stretch-activated and stretch-inactivated ion channels,
are characterized by a change in open probability
(Po) on membrane deformation. Mechanosensitive ion channels are found in a large variety of vertebrate and
nonvertebrate cells, including smooth muscle (6, 8,
12-13). A mechanosensitive, stretch-activated, L-type
Ca2+ channel has been characterized in human jejunal
circular smooth muscle cells (3). Activation of this
channel by positive pressure applied to the recording pipette, or by an
increase in shear stress on the cell membrane, resulted in an increase
in whole cell Ca2+ current. The increase in whole cell
Ca2+ current is blocked by the L-type Ca2+
channel blocker nifedipine. At a single channel level, negative pressure applied to an on-cell patch through the recording pipette resulted in activation of an ~16 pS nifedipine-sensitive
Ca2+ channel.
Ca2+ entry through L-type Ca2+ channels is the
major pathway through which Ca2+ enters gastrointestinal
smooth muscle cells to activate the contractile apparatus. In the
presence of nifedipine, intestinal smooth muscle contractile activity
is decreased markedly. Previous experiments on the mechanosensitive,
stretch-activated, L-type Ca2+ channel were carried out
with Cs2+ in the recording pipette to block K+
current and at a hyperpolarized holding voltage (
100 mV) to accentuate inward Ca2+ current (3). Under
these recording conditions, it was not possible to determine the
effects of Ca2+ entry through mechanoactivation of L-type
Ca2+ channels on membrane potential, outward current, and
the contractile state of human jejunal circular smooth muscle cells.
Therefore, the aims of this study were to determine the effects of
mechanical stimulation of human jejunal circular smooth muscle cells on
membrane potential and outward current using K+-containing
pipette solutions and less-hyperpolarized holding voltages.
 |
METHODS |
Use of human jejunum, approved by the Institutional Review
Board, was obtained as surgical waste tissue during gastric bypass operations performed for morbid obesity. Tissue specimens were harvested directly in chilled buffer with warm ischemia times of ~30
s. Single, isolated, relaxed circular smooth muscle cells were obtained
from the human jejunal specimens as previously described (4,
5).
Patch-clamp recordings.
Whole cell patch-clamp recordings were made using standard and
amphotericin perforated-patch-clamp whole cell techniques. Whole cell
and single channel recordings were obtained using Kimble KG-12 glass
pulled on a P-97 puller (Sutter Instruments, Novato, CA). Electrodes
were coated with R6101 (Dow Corning, Midland, MI) and were fire
polished to a final resistance of 3-5 M
. Currents were
amplified, digitized, and processed using an Axopatch 200A amplifier, a
Digidata 1200, and pCLAMP 8 software (Axon Instruments, Foster City,
CA). Whole cell records were sampled at 2 kHz and filtered at 1 kHz
with an eight-pole Bessel filter using the pulse protocols shown in
Figs. 1-7. Single channel records were sampled for 60 s at 5 kHz and were filtered at 2 kHz with an eight-pole Bessel filter. The
pulse protocols used are shown in Figs. 1-7. Drugs were applied by
complete bath changes with the solution containing the drug. Bath
perfusion at 10 ml/min for 30 s was used to create shear stress
and activate the mechanosensitive L-type Ca2+ channels
according to a previously established protocol (3). Of the
three methods (perfusion, positive pressure, negative pressure in
on-cell mode) previously used to activate mechanosensitive Ca2+ channels, perfusion was chosen, since it may most
closely mimic the effects of movement of the extracellular matrix and
adjacent smooth muscle on ion channels present on the cell surface. It was also used because of the marked repeatability of its effects. Cell
length was determined from digitized images taken before, during, and
after perfusion. Single channel records were obtained from on-cell
patches with either normal Ringer solution or 150 mM K+ in
the bath. Large-conductance Ca2+-activated
K+ channels were identified by their large conductance,
voltage dependence, and charybdotoxin sensitivity. The voltage applied to the pipette (Vpipette) values were chosen so
that only one to two channels in each patch were open at rest.
All records were obtained at room temperature (22°C). Records were
not leak subtracted because the mean input resistance at
80 mV was
19 ± 4 G
.

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Fig. 1.
Effect of bath perfusion at 10 ml/min on outward
K+ current. Whole cell currents were recorded with
K+ in the pipette to record outward current and membrane
potential (A) using the pulse protocol shown in the
inset. B: bath perfusion increased outward
K+ current from 680 to 841 pA at +60 mV. C: 4 min after bath perfusion, outward current (at +60 mV) decreased to 719 pA. Bath perfusion hyperpolarized the membrane potential from 52 to
64 mV. D: membrane potential depolarized back to 53 mV 3 min after perfusion. , Control; ,
perfusion; , 4 min postperfusion. E: time
course of the changes in membrane potential. The mean change in outward
K+ current (inset) was from 664 ± 57 to
773 ± 72 pA; n = 14 patches, *P < 0.0002. Open bars, control; filled bars, perfused. The membrane
potential hyperpolarized from 42 ± 4 to 50 ± 5 mV
(P < 0.01).
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Fig. 2.
A: effect of bath perfusion at 10 ml/min on
inward Ca2+ current and outward K+ current.
Currents were recorded using the pulse protocol shown in the
inset. In 50% of cells recorded with K+ in the
pipette, an inward Ca2+ current was discernible.
B: bath perfusion increased inward Ca2+ current
in this cell from 17 to 31 pA (inset; scale for
insets same for both A and B). Outward
current increased from 480 to 525 pA in the recording shown, which was
obtained 30 s after initiation of perfusion, and peaked 90 s
after initiation of perfusion.
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Fig. 3.
Effect of block of the mechanosensitive Ca2+
channel by nifedipine (10 µM) in bath on outward K+
current. Currents were recorded using the pulse protocol shown in the
inset between A and B. In the presence
of nifedipine (A), perfusion did not increase outward
K+ current (1,465 to 1,488 pA at +60 mV; B) and
did not change membrane potential ( 44 to 43 mV; C).
, Control in the presence of nifedipine;
, perfusion. The mean change in outward current
(inset in C) was from 694 ± 133 to 713 ± 132 (n = 9 patches, P > 0.05), and
the mean change in membrane potential was from 47 ± 5 to
48 ± 6 mV (P > 0.05; inset in
C). Open bars, control; filled bars, perfusion with
nifedipine.
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Fig. 4.
Effect of block of large-conductance
Ca2+-activated K+ channels on the
perfusion-induced increase in outward current. Currents were recorded
using the pulse protocol shown in the inset. Addition of
charybdotoxin (100 nM) to the bath decreased outward current
(A, control; B, charybdotoxin). In the presence
of charybdotoxin, perfusion of the bath did not increase outward
current (C; 573 to 561 pA) or change membrane potential
(D; 38 to 39 mV). , Control;
, charybdotoxin; , perfusion in the
presence of charybdotoxin. The mean change in outward current in the
presence of charybdotoxin was from 550 ± 32 to 518 ± 49 pA
(inset in D), and the mean change in membrane
potential was from 39.3 ± 2 to 42.0 ± 2 mV
(n = 7, P > 0.05; inset in
D). Open bars, control; filled bars, perfusion with
charybdotoxin.
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Fig. 5.
Effect of perfusion on large-conductance Ca2+-activated
K+ channel open probability (Po).
A: preperfusion; B: postperfusion. Records were
obtained from an on-cell patch with 150 mM K+ in the
pipette and normal Ringer solution in the bath. Normal Ringer solution
was perfused at 10 ml/min for 30 s to activate mechanosensitive
L-type Ca2+ channels; 1-min records were obtained at a
pipette voltage of 40 mV immediately before and after perfusion. No
voltage command was applied between records. NPo
(where N = no. of channels present in patch) was 0.01 before
and 0.08 after perfusion. O, open; C, closed. Single channel
conductance in this patch was 93 ± 5 pS.
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Fig. 6.
Effect of perfusion on cell length. A: human jejunal
circular smooth muscle cell just before perfusion of normal Ringer
solution. B: during perfusion (10 ml/min for 30 s).
C: ~30 s after perfusion was stopped. Size of the line is
the same for each panel. Perfusion decreased cell length by 11%, which
reversed when perfusion was stopped.
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Fig. 7.
Proposed model. Mechanoactivation of L-type
Ca2+ channels (CaL) in human jejunal circular
smooth muscle cells increases Ca2+ entry (A and
B) and activates the contractile apparatus (C).
Ca2+ entry subsequently activates large-conductance
Ca2+-activated K+ channels (KCa),
resulting in an increase in outward K+ current
(D), membrane hyperpolarization (E), and
relaxation (F).
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Drugs and solutions.
The pipette solution contained (in mM) 150 K+, 20 Cl
, 2 EGTA, 5 HEPES, and 130 methanesulfonate. The bath
solution contained (in mM) 146 Na+, 4.7 K+,
154.7 Cl
, 2 Ca2+, and 5 HEPES (normal Ringer
solution) for whole cell records and 146 Na+, 4.7 K+, 154.7 Cl
, 2 Ca2+, and 5 HEPES
or 150 K+, 154 Cl
, 2 Ca2+, and 5 HEPES for single channel records. Drugs were purchased from Sigma
Chemicals (St. Louis, MO).
Data analysis.
Data were analyzed using pCLAMP 8 software or custom macros in Excel
(Microsoft, Redmont, WA). Whole cell currents were quantified at +60
mV. The final 200-ms segment of each trace was averaged to determine
mean values.
Membrane potential was determined by a custom algorithm that took three
points from the current-voltage relationship at the point where the
current changed from negative to positive (that is, the point closest
to zero current, the previous point with a negative current value, and
the next point with a positive current value). A fit was drawn through
the three points, and the voltage at zero current was reported as the
membrane potential. The observed values were identical to membrane
potentials recorded in current-clamp mode. Values were adjusted for the
junction potential.
Paired Student's t-test was used to evaluate statistical
significance. Single channel Po was determined
from all-points amplitude histograms. Because multiple
large-conductance Ca2+-activated K+ channels
were present in most patches recorded from, Po
was expressed as NPo (where N = number of channels present in the patch). Values in text are presented
as means ± SE.
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RESULTS |
Perfusion activates an outward K+ current.
Outward current (measured at +60 mV) increased from 664 ± 57 pA
before bath perfusion to 773 ± 72 pA (n = 14, P < 0.0002) after bath perfusion (10 ml/min normal
Ringer, Fig. 1) in both standard whole
cell and perforated-patch experiments. No difference was noted in the
increase in outward current in response to perfusion between standard
whole cell and perforated-patch experiments (644 ± 112 to
763 ± 137 pA, n = 7, and 683 ± 38 to
789 ± 59 pA, n = 7, respectively,
P > 0.05). An increase in outward current was noted in
13 of 14 cells tested and at all voltages positive to
40 mV. The
voltage at zero current (resting membrane potential) was
42 ± 4 mV and hyperpolarized to
45 ± 4 mV 1 min after bath perfusion
and
48 ± 4 mV 2 min after perfusion (P < 0.05). The mean maximal hyperpolarization was
50 ± 5 mV
(P < 0.05). At 4 min after perfusion, membrane
potential depolarized back to preperfusion values (
40 ± 7 mV).
An initial increase in outward current was noted within 30 s of
perfusion, reached maximal levels at 80 ± 20 s, and returned
to baseline at 187 ± 30 s. In 7 of 14 cells, an inward
current could be seen at the beginning of the current trace (Fig.
2). The maximal transient inward current
was 18 ± 6 pA and increased (in all cells) to 30 ± 12 pA
(n = 7, P < 0.05) with perfusion,
consistent with mechanoactivation of Ca2+ channels as
previously reported (3). Maximal perfusion-activated outward
current was recorded 30 ± 11 s after maximal inward
Ca2+ current was measured. In a separate series of
experiments, cells were initially perfused at 1 ml/min, and then the
perfusion rate was increased to 10 ml/min. The outward current
increased in a dose-dependent manner with an increase from 620 ± 191 to 669 ± 197 pA at 1 ml/min (P < 0.05, n = 4) and to 716 ± 205 pA at 10 ml/min
(P < 0.05, n = 4, data not shown).
Nifedipine (10 µM) was used to determine if the increase in outward
current was secondary to increased Ca2+ entry through
mechanosensitive L-type Ca2+ channels or due to activation
of a second, mechanosensitive channel. On bath perfusion (10 ml/min) in
the presence of nifedipine, there was no change in outward current
(694 ± 133 to 713 ± 132 pA, n = 9, P > 0.05) or change in membrane potential (
47 ± 5 to
48 ± 6 mV, P > 0.5, Fig.
3).
The Ca2+ dependence of the activated outward current and
the "noisiness" of the current traces suggested involvement of
large-conductance Ca2+-activated K+ channels.
Charybdotoxin (100 nM), a Ca2+-activated K+
channel blocker, was used to test this possibility in amphotericin perforated-patch experiments. In the presence of charybdotoxin, bath
perfusion (10 ml/min) did not increase outward current (550 ± 32 to 518 ± 49 pA, n = 7, P > 0.05, Fig. 4) or change membrane potential
(
39 ± 2 to
42 ± 2 mV, n = 7, P > 0.5). Charybdotoxin not only blocks
large-conductance Ca2+-activated K+ channels
but also blocks intermediate-conductance Ca2+-activated
K+ channels (1) and a limited subset of
small-conductance Ca2+-activated K+ channels
(1). Therefore, the effects of iberiotoxin, a specific blocker of large-conductance Ca2+-activated K+
channels on the perfusion-induced increase in outward current, were
tested. In the presence of iberiotoxin (200 nM), bath perfusion did not
increase outward current (687 ± 77 to 680 ± 63 pA,
n = 6, P > 0.05) nor hyperpolarize the
membrane potential (
50 ± 5 to
48 ± 6 mV,
P > 0.05, data not shown). In contrast, in the presence of charybdotoxin (100 nM, n = 4) or
iberiotoxin (200 nM, n = 1), perfusion (10 ml/min)
still evoked an increase in inward Ca2+ current (49 ± 23% increase, n = 5, P < 0.05),
suggesting that the changes in Ca2+ current were
independent of changes in K+ current (data not shown).
Nifedipine has been shown to inhibit a K+ channel, hKv1.5
(15). To determine if nifedipine had a direct effect on
K+ currents in human jejunal circular smooth muscle cells,
nifedipine (1 µM) was added to the bath after incubation with
iberiotoxin (200 nM). Nifedipine had no effect on outward
K+ current (654 ± 108 to 627 ± 95 pA,
n = 4, P > 0.05, data not shown).
Perfusion increases in Po of large-conductance
Ca2+-activated K+ channels.
Single channel recordings of large-conductance
Ca2+-activated K+ channels were obtained from
on-cell patches. Initial experiments were carried out with 150 mM
K+ in the bath to control the membrane potential (0 mV).
Under these recording conditions, no change in
Po of large-conductance
Ca2+-activated K+ channels was seen after a
30-s perfusion of the bath with a solution containing 150 mM
K+. This was likely secondary to L-type Ca2+
channel inactivation at membrane potentials ~0 mV. Therefore, subsequent experiments were carried out using normal Ringer solution in
the bath and perfusate. Perfusion (10 ml/min for 30 s) of a human
jejunal circular smooth muscle cell with normal Ringer solution increased NPo of large-conductance
Ca2+-activated K+ channels from 0.01 to
0.08 (Fig. 5,
Vpipette =
40 mV); the values were
measured immediately after perfusion was stopped. The mean increase in
NPo of the large-conductance
Ca2+-activated K+ channels was 3.8-fold
(n = 5 patches).
Human jejunal circular smooth muscle cells contract in response to
perfusion.
Digitized images of whole cell currents were obtained from cells just
before perfusion at 1 and 10 ml/min, ~15 s into perfusion, and again
~30 s after perfusion. Perfusion at 1 ml/min decreased maximal cell length by 5 ± 2% (n = 6, P < 0.05), and perfusion at 10 ml/min decreased length
by 14 ± 3% (n = 11, P < 0.05, Fig. 6). In a separate series of
experiments, cells (n = 10, data not recorded) were
perfused after preincubation with nifedipine (1 µM). In the presence
of nifedipine, perfusion did not change cell length (data not shown).
 |
DISCUSSION |
The present study suggests a functional link between
mechanoactivated L-type Ca2+ channels and large-conductance
Ca2+-activated K+ channels. Large-conductance
Ca2+-activated K+ channels in mesenteric artery
smooth muscle cells (2) and in the ascending limb of the
kidney (10) exhibit mechanosensitivity. The data presented
in this report suggest that large-conductance Ca2+-activated K+ channels in human jejunal
circular smooth muscle cells are not mechanosensitive themselves but
are activated by an increase in intracellular Ca2+ that is
modulated by mechanosensitive L-type Ca2+ channels.
Ca2+-activated K+ channels can be divided into
the following three main groups: voltage-insensitive small- conductance
(~1-20 pS; SK), voltage-insensitive intermediate-conductance
(~10-50 pS; IK), and voltage- sensitive large-conductance
(~100-650 pS; BK) Ca2+-activated K+
channels (1). SK and BK channels are often coexpressed in a variety of cells (1). SK channels are an order of
magnitude more Ca2+ sensitive than IK or BK channels
(1), suggesting that, if present in human jejunal circular
smooth muscle cells, they too would be activated by Ca2+
entry through mechanosensitive L-type Ca2+ channels. IK
channels have been described in murine ileal and colonic myocytes, and
SK channels have been described in ileal myocytes (9, 14).
However, it is unknown whether SK and IK channels are expressed in
human jejunal circular smooth muscle cells. BK and some IK channels are
known to be charybdotoxin sensitive, but most SK channels are
charybdotoxin insensitive (1). In the present study,
charybdotoxin and iberiotoxin completely blocked the increase in
outward K+ current induced by perfusion. Also, perfusion
activated a large-conductance K+ channel in on-cell
patches. Therefore, it is likely that the major effect of
Ca2+ entry on K+ current through L-type
mechanosensitive Ca2+ channels was due to activation of BK
in human jejunal circular smooth muscle cells, although smaller effects
on SK and IK cannot be excluded.
It has been proposed previously that large-conductance
Ca2+-activated K+ channels and L-type
Ca2+ channels are linked functionally. In rabbit basilar
artery myocytes, Ca2+ influx through L-type
Ca2+ channels open at the resting membrane potential
results in contraction and subsequent activation of large-conductance
Ca2+-activated K+ channels, leading to
fluctuations in contractile tone of myogenic origin (11).
In the presence of charybdotoxin, the cyclic changes in myogenic tone
are replaced by a tonic contraction. The mechanism triggering
Ca2+ influx through L-type Ca2+ channels could
not be elucidated in the above study. A close functional link between
L-type Ca2+ channels and large-conductance
Ca2+-activated K+ channels was also
demonstrated in rabbit coronary myocytes (7). In this
study, opening of L-type Ca2+ channels was shown to
stimulate adjacent large-conductance Ca2+-activated
K+ channels by increasing Ca2+ concentration in
a local submembrane Ca2+ pool dissociated from bulk
cytosolic Ca2+. In the present study, a similar mechanism
is proposed. The temporal relationship between the L-type
Ca2+ current and the outward K+ current, with
maximal inward Ca2+ current recorded ~30 s before
maximal outward K+ current and the block of activation of
adjacent large-conductance Ca2+-activated K+
channels by block of L-type Ca2+ channels, supports this
hypothesis. Additionally, a trigger for initial Ca2+ entry
is proposed to be mechanical stimulation of mechanosensitive Ca2+ channels.
The present study suggests a signaling pathway involving interaction of
a novel, mechanosensitive L-type Ca2+ channel, the
contractile apparatus of the human jejunal circular smooth muscle cell,
and large-conductance Ca2+-activated K+
channels. Interaction between these signaling elements (Fig. 7), as may occur during normal digestive
activity or in pathological obstructive disorders, results in
transduction of mechanical energy into Ca2+ influx through
mechanosensitive Ca2+ channels and subsequent contraction.
Mechanoactivation of L-type Ca2+ channels may provide a
mechanism by which the myocyte can act as both a motor and sensory
organ. Contraction is limited by activation of large-conductance
Ca2+-activated K+ channels, membrane
hyperpolarization, and L-type Ca2+ channel inactivation.
Membrane hyperpolarization results in a decrease in the
Po of L-type Ca2+ channels, a
decrease in intracellular Ca2+, and muscle relaxation.
Whether release of intracellular Ca2+ also participates in
this signaling pathway remains to be determined.
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ACKNOWLEDGEMENTS |
We thank Gary Stoltz for technical assistance and Kristy Zodrow and
Jan Applequist for secretarial assistance.
 |
FOOTNOTES |
This work was supported by National Institute of Diabetes and Digestive
and Kidney Diseases Grants DK-17238, DK-52766, and DK-39337.
Address for reprint requests and other correspondence: G. Farrugia, 8 Guggenheim Bldg., Mayo Clinic, 200 First St. SW, Rochester, MN 55905 (E-mail: farrugia.gianrico{at}mayo.edu).
The costs of publication of this
article were defrayed in part by the
payment of page charges. The article
must therefore be hereby marked
"advertisement"
in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.
Received 6 March 2000; accepted in final form 30 June 2000.
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