Calcium-activated nonselective cationic channel in macula densa cells
Jean-Yves Lapointe,1
P. Darwin Bell,2
Ravshan Z. Sabirov,3 and
Yasunobu Okada3
3National Institute for Physiological Sciences,
Okazaki 444-8585, Japan; 1Group de Recherche en
Transport Membranaire, University of Montreal, Montreal, Quebec H3C 3J7,
Canada; and 2Nephrology Research and Training Center,
University of Alabama at Birmingham, Birmingham, Alabama 35294
Submitted 30 August 2002
; accepted in final form 21 April 2003
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ABSTRACT
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Patch-clamp experiments in cell-attached (c/a) and inside-out (i/o)
configurations were performed to directly observe ionic channels in lateral
membranes of macula densa (MD) cells from rabbit kidney. In the presence of
140 mM KCl in the pipette and normal Ringer solution in the bath, we
repeatedly observed in c/a and in i/o configurations a 20- to 23-pS channel
with a linear current-voltage (I-V) relationship reversing
near 0 mV. Ionic replacement in the bath solution clearly indicated a cationic
selectivity but with equal permeability for Na+ and K+.
Single-channel kinetics was characterized by higher open probability at
positive membrane potentials. In i/o experiments, elimination of bath
Ca2+ (
1 µM) abolished channel activity in a
reversible manner. This MD nonselective cationic channel was found to display
a certain Ca2+ permeability because single-channel
events could be detected when the pipette potential was very negative
(60, 80, and 100 mV) in the presence of 73 mM
CaCl2 in the bath solution. The similarities between this channel
and some channels of the transient receptor potential family suggest a
possible role for this MD basolateral channel in controlling membrane
potential and regulating Ca2+ entry during MD cell
signaling.
transient receptor potential channels; intracellular calcium; patch clamp; tubuloglomerular feedback; nifedipine
THE MACULA DENSA (MD) plaque is a group of epithelial cells
located in the cortical thick ascending limb (CTAL) in close proximity to the
juxtaglomerular apparatus. This constitutes a unique anatomic arrangement
where the vascular and the epithelial networks of the kidney come into
contact. The recognized role of MD cells is to detect increases in tubular
luminal fluid NaCl concentration ([NaCl]L) and transmit signals,
resulting in a decrease in glomerular filtration rate (through a contraction
of the afferent arteriole) and an increase in renin secretion (by the granular
cells of the afferent arteriole)
(28). We and others have
worked toward identifying the various transport pathways expressed in MD cells
to further our understanding of the steps involved in the generation of
tubuloglomerular feedback (TGF) signals. The initial step in TGF is the
detection of a rise in [NaCl]L by the furosemide-sensitive apical
Na-K-2Cl cotransporter (13,
16,
27), followed by
depolarization of the basolateral membrane
(2,
27), cellular alkalinization
(6), and a modest but
significant rise in intracellular Ca2+ concentration
([Ca2+]i) that is nifedipine sensitive
(25). Recent work suggests
that the final transport step at the MD is the release of ATP across the
basolateral membrane and through a maxianion channel
(3). Whether ATP serves as the
final mediator that elicits afferent arteriolar vasoconstriction, or if there
is the requirement for the generation of adenosine, is still being debated
(28).
Over the last decade, substantial progress has been made in understanding
the membrane properties of MD cells, especially by applying
electrophysiological and epifluorescence techniques
(15). In previous studies, we
used patch-clamp techniques to identify a K+ channel on the apical
membrane of MD cells by carefully excising and removing that portion of the
CTAL covering the MD apical membrane
(8). More recently
(3), we have removed the entire
CTAL that surrounds the MD plaque, thereby providing an access to the lateral
membrane. Using this preparation, we now report the existence of a
nonselective cation (NSC) channel in MD cells that is
Ca2+ activated and Ca2+ permeable.
This channel is proposed to play a role in the regulation of
[Ca2+]i and basolateral membrane potential in
MD cells.
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MATERIALS AND METHODS
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Tubule preparation. Studies were performed using renal tubules
dissected from New Zealand White rabbits as described in previous publications
from this laboratory (8,
1216).
Mid-CTAL with attached glomeruli were isolated by manual dissection at a
magnification of x80. The CTAL covering the MD plaque was completely
removed, leaving the MD plaque attached to the glomerulus. This maneuver
provided direct access for patch clamping both the apical and lateral
membranes of MD cells. Free access to the lateral membrane is supported by our
previous observation of a maxi-Cl channel likely to be
involved in the basolateral ATP release
(3). The MD-glomerulus was
transferred to an inverted microscope; a holding pipette was used to stabilize
the MD plaque and position it for access by the patch pipette. Changes in the
bath solution were performed, at room temperature, using a rate of 1520
ml/min for a minimum of 45 s, corresponding to >10 times the bath volume.
Table 1 gives the composition
of the bath and pipette solutions.
Patch clamping. Channel activity was recorded with standard
patch-clamp techniques (7)
using either an Axopatch 2000 (Axon Instruments, Foster City, CA) or EPC-7
amplifier (HEKA Elektronik, Lambrecht, Germany). Recordings were low-pass
filtered at 2 kHz, digitized at 1 ms/point, and stored on a hard disk using a
commercial acquisition system (Pclamp6, Axon Instruments). Pipettes were
pulled from soft glass capillaries (Fisher Scientific, Pittsburgh, PA) using a
two-step vertical puller (model PP-83, Narishige, Tokyo, Japan) or a
multiple-step horizontal puller (model P-97, Sutter Instruments, Novato, CA).
When filled with pipette solution (see
Table 1), pipette resistance
was between 2 and 5 M
.In inside-out (i/o) experiments, membrane
potential is reported as Vp, where
Vp is the pipette potential. In cell-attached (c/a)
experiments, membrane potential can be estimated from
Vp + actual cellular potential difference. At room
temperature, in the presence of 150 mM NaCl bath solution, this cellular
potential is expected to be quite low; an average of 25 mV in the
presence of an intact CTAL microperfused at 39°C with 150 mM NaCl has
previously been reported (2,
12). When channel activity was
observed, a pulse protocol consisting of 11 voltage pulses (4 s in duration)
was initiated using potentials from 100 to +100 mV in 20-mV increments.
In selected experiments, the mean channel activity (NPo
where N is the number of channels in the membrane patch, and
Po is the channel open probability) was estimated by
measuring the average "macroscopic" current during each 4-s
voltage pulse. Leak currents were estimated from current levels recorded when
all channels were closed and confirmed by observing its monotonous variation
when the membrane potential was changed from 100 to +100 mV. Dividing
the net channel current by the single-channel current amplitude yields an
estimate of NPo. Estimation of permeability ratios between
monovalent cations was obtained from the Goldman-Hodgkin-Katz equation. For
monovalent cations, permeability ratios
(Pcation/PNa) are calculated from the
reversal potential (VR) which is given by
 | (1) |
where p and c stand for the indicated cation concentration in the pipette and
on the cytosolic side, respectively, NMDG is for
N-methyl-D-glucamine, and R, T, and F
have their usual meaning. The permeability ratio
PCa/PCat (where Cat stands for either
Na or K) was evaluated from the reversal potential observed in the presence of
a high-Ca2+ concentration ([Ca2+])
solution on the cytosolic side and the normal pipette solution on the
extracellular side (see Table
1) using the following equation derived from the constant field
approximation (33)
 | (2) |
Statistics. Data are presented as means ± SE and n
is the number of single-channel recordings analyzed. Statistical significance
of the difference between two means was assessed using Student's
t-test for paired samples. P < 0.05 was considered
significant.
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RESULTS
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During patch clamp of the lateral membranes of MD cells, several different
channels were identified, including small (1025 pS) and intermediate
conductance levels (3050 pS) as well as a maxi-Cl
channel (
380 pS) (3). In
the present study, we will specifically deal with a small-conductance channel
(2023 pS) that could be repeatedly seen in the lateral membrane of MD
cells.
C/a mode. Figure 1
shows representative single-channel events and an average current-voltage
(I-V) curve obtained from seven c/a patches during the
±100-mV pulse protocol in a normal Ringer bath. In each case, the
I-V relationship was linear, yielding a mean conductance of
20.6 ± 0.6 pS (n = 7). At this stage of the experiment, care
was taken to eliminate lower conductance channels (12-16 pS) or the maxianion
channel that was sometimes observed in c/a patches. The
20-pS channel
displayed a higher Po and a larger mean open time at
positive membrane potentials. In a high-K+ bathing solution (see
Table 1), the
I-V relationship in c/a mode remained linear (conductance =
20.7 ± 0.9 pS, n = 4, data not shown) and continued to reverse
near 0 mV, suggesting that the cellular potential was probably low and
insensitive to a rise in external K+ concentration from 5 to 80
mM.

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Fig. 1. Single-channel events in cell-attached configuration for macula densa cells
bathed in normal Ringer solution. A: single-channel recordings as a
function of minus pipette potential (Vp).
B: average single-channel current-voltage (I-V)
curve from 7 different patches. G, mean conductance.
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I/o mode/selectivity. In i/o experiments, full
I-V curves were obtained before and after the bathing
solution was changed from Ringer to the low-Na+ solution and/or to
the high-K+ solution (see Table
1 for compositions). The single-channel conductance in Ringer
averaged 23 pS (n = 8), and the average current reversed at 0.1 mV
(see Fig. 2). When cytosolic
Na+ was lowered by an order of magnitude (from 135 to 13.5 mM), the
VR increased to +25.5 mV (n = 5), indicating that
the channel was more permeable to Na+ than to NMDG+. The
VR observed in Ringer (always with 140 mM KCl in the
pipette) suggests a PK/PNa
permeability ratio of 1.0. Using this value, the VR
observed in the low-Na+ solution yields a
PNMDG/PNa of 0.27. In contrast, when
the cytosolic solution was changed from Ringer to high K+,
VR was displaced by only +3.5 mV (n = 6). This is
in agreement with a PK/PNa
1 and
a reduction in the cytosolic Na++K+ concentration from
140 mM in the Ringer solution to 110 mM in the high-K+ solution
(see Table 1). As expected from
a cationic channel, reducing cytosolic Cl by one order of
magnitude did not affect the single-channel I-V curve
(n = 4, data not shown). This 20- to 23-pS channel, with a
Po that increases with depolarization, can be functionally
described as an NSC channel.
Intracellular Ca2+ sensitivity. As shown in
Figs. 3 and
4, the NSC channel required
Ca2+ on the cytosolic surface to remain active. In i/o
experiments, channel activity was completely lost on perfusion with either a
Ca-free (0Ca)-EGTA solution (n = 6; pCa
8.7, assuming <30
µM Ca2+ in double-distilled water,
Table 1) or with a 1 µM
(n = 3; pCa6 solution, Table
1). The channel could be fully reactivated when normal Ringer was
reintroduced into the bath (see Fig.
3A). The NPo was measured in i/o
configuration with sequential exposure to Ringer solution and a
low-Ca2+ solution (either 0Ca-EGTA solution or the pCa6
solution). As shown in Fig.
3B, calculated NPo values were
significantly decreased for positive membrane potentials. Average
NPo for all positive membrane potentials gave a value for
NPo of 1.1 in Ringer solution that was significantly
reduced to 0.16 in the low-Ca2+ solution (P
< 0.01, n = 5).

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Fig. 3. Reversible effect of removing Ca2+ from the cytosolic
surface on cationic channel activity in i/o patches. A:
single-channel recordings as a function of the membrane potential (i.e.,
Vp) in the presence of 140 mM KCl in the pipette
and either Ringer (2 mM
Ca2+)orCa2+-free (0Ca)-EGTA
solution in the bath. Arrows indicate the 0-current level for the 3 sets of
traces. B: average (of 5 experiments) open probability of the channel
(NPo, where N indicates the no. of channels
present) as a function of Vp. Values are means
± SE of 5 observations.
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Fig. 4. Channel activity during administration of 10 µM nifedipine and low
Ca2+ concentration (1 µM) to the cytosolic surface in
i-o experiments. A: recordings obtained from the same patch
sequentially exposed to Ringer, nifedipine (a 2nd Ringer is not shown),
low-Ca2+ Ringer, and then Ringer. It is shown that 1
µM Ca2+produced the same inhibition that was
previously found with the 0Ca-EGTA solution; however, the inhibitory effects
of nifedipine were marginal. B: average NPo as a
function of Vp. The inhibitory effect of nifedipine
failed to reach statistical significance (P = 0.11, n =
4).
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Nifedipine sensitivity and divalent cation permeability. Because
certain members of the NSC channel family mediate Ca2+
influx, we tested the possibility that this channel would be directly
responsible for the nifedipine-sensitive basolateral pathway that mediates MD
[Ca2+]i increase after a rise in
[NaCl]L (25). In a
series of four i/o experiments, the presence of a
Ca2+-sensitive small-conductance channel was first
positively identified by reducing bath solution Ca2+
concentration (using either 0Ca-EGTA or the pCa6 solution) before a return to
Ringer solution and addtion of 10 or 20 µM nifedipine. As illustrated in
Fig. 4, this large
concentration of nifedipine failed to inactivate this channel. It was found
that NPo was not significantly reduced by the addition of
nifedipine (see Fig.
4B). In a consideration of all positive membrane
potentials, average NPo was 1.1 in the presence of Ringer
solution and decreased to 0.6 in the presence of nifedipine (P =
0.11, n = 4).
To test for divalent cation permeability of the channel, we tested the
effects of a 73 mM CaCl2 solution (n = 4,
Table 1). Application of the 73
mM CaCl2 solution to the cytosolic surface produced a major
decrease in NPo for both positive and negative membrane
potentials (see Fig.
5A). While a few brief openings could be detected at
negative membrane potentials (presumably K+ flowing from the
pipette to the bath, see Fig.
5B, trace 3), there were also several
single-channel openings, having current amplitudes of 0.6 to 1.3 pA, at
membrane potentials of +60, +80, and +100 mV (see
Fig. 5B, traces
1 and 2). Figure
5C, the I-V relationship for
single-channel currents in the presence of the 73 mM CaCl2 solution
on the cytosolic surface, shows that single-channel conductance has decreased
by a factor of
2.5. In one case (+ in
Fig. 5C),
Ba2+ was used instead of Ca2+ in
the bath solution, and very similar single-channel outward currents could be
observed. In Fig. 5C,
we pooled the single-channel currents observed in five experiments and
performed a linear fit of the data. In the presence of 73 mM
Ca2+ (or Ba2+) on the cytosolic
side and 140 mM K+ on the external surface, Eq. 2 predicts a
VR of nearly 1 mV if K ions and divalent cations
have identical permeabilities. As the VR was around +9mV,
PCa/PK is estimated at
0.6.

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Fig. 5. Single-channel recording in i-o configuration with 140 mM KCl in the patch
pipette and 73 mM CaCl2 in the bath or cytosolic solution.
A: recordings of 4 s in duration at different membrane potentials
from 100 to +100 mV. B: enlargement of the 3 portions of the
recordings depicted in A (13). C:
I-V relationship for single-channel currents (outward are
Ca2+ currents) obtained from single-channel events
observed in 5 different patches where a pulse protocol similar to the one
shown in A was used.
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DISCUSSION
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The present studies report the presence of a NSC channel of low conductance
in MD cells that is 1) activated by intracellular
Ca2+, 2) nifedipine insensitive, and
3) Ca2+ permeable. The density of this channel
in rabbit MD cells was relatively high because it was found in approximately
one-half of the patches that were positive for channel activity. Before
speculating on the role of such a channel in the physiology of MD cells, let
us first compare its properties with those of similar channels found in other
epithelial cells.
Comparison with other NSC channels observed in epithelial cells.
Low-conductance NSC channels have been reported in several tissues, including
several segments of the mammalian nephron, primary cultures of renal
epithelial cells, and renal cell lines. Of particular interest is the 23- to
27-pS NSC channel that was reported by Chraibi et al.
(5) in the basolateral membrane
of practically all segments of the mouse nephron, from the proximal tubule to
the outer medullary collecting duct. The characteristics of this channel
include 1) linear I-V curve in i/o configuration;
2) equal permeability to Na+ and K+;
3) NPo increase with membrane depolarization; and
4) requirement for channel activity in i/o configuration of 0.1 to 1
mM [Ca2+] on the cytosolic surface. All of these
characteristics are compatible with the NSC channel found in MD cells.
Remarkably similar channels (22- to 25-pS conductance, nonselectivity, and
[Ca2+]i >1 µM required for channel
activation) were observed on the apical membrane of proximal tubule cells in
primary culture (19), in a
cortical collecting tubule cell line
(10), and in inner medullary
collecting duct cell lines
(18,
24,
30). Interestingly, in the
cortical collecting duct cell lines, the NSC channel was found to be activated
by cell shrinkage (31) whereas
in the inner medullary cell line these channels were activated by cell
swelling (24). More recently,
a cationic channel of similar conductance (22.8 pS) and poor selectivity was
reported in the apical membrane of freshly isolated outer medullary collecting
duct cells of the rabbit (32).
This channel appears distinct from the MD NSC channel because it was fully
functional in the absence of cytosolic Ca2+ (0Ca-EGTA
solution) in i/o patches. Specific roles for NSC channels are difficult to
establish, but it was suggested that NSC channels could be involved in
Na+ reabsorption, K+ secretion, and volume
regulation.
Transient receptor potential channels. Channels from the transient
receptor potential (TRP) family are ubiquitously distributed and considered to
be responsible for capacitive Ca2+ entry (CCE), which is
activated after intracellular Ca2+ release. First cloned
from Drosophila (22),
the TRP gene family codes for at least 20 mammalian homologues
(4,
21,
23), with single-channel
conductances ranging from 2023 pS for human TRPC3
(4,
9) to 110 pS for the homologous
TRPl proteins (TRP-like) (11).
In general, these channels have poor selectivity with respect to monovalent
cations, and some of them are permeable to divalent cations
(9,
20,
29,
34). Among the four TRP
channels expressed in the kidney, only TRPM4 codes for an NSC channel
(20). The functional
properties of a splice variant named TRPM4b have been recently presented
(17). Northern blot analysis
revealed the presence of specific TRPM4b transcripts in various tissues,
including heart, liver, pancreas, placenta, and kidney
(17). Interestingly, TRPM4b
transfected into HEK-293 cells yields a 25-pS NSC channel with a nearly linear
I-V curve and an open probability that increases with cell
depolarization. This channel, which was not found to be
Ca2+ permeable in whole cell experiments, was activated
by agonist-induced rises in [Ca2+]i. Compared
with measurements of membrane potential and
[Ca2+]i in nontransfected HEK-293 cells,
release of intracellular Ca2+ in transfected HEK-293
cells triggers cell depolarization through the activation of TRPM4b that, in
turn, causes a decrease in the driving force for Ca2+
entry. It was proposed that TRPM4b serves in the regulation of membrane
potential after intracellular Ca2+ release.
Putative role of the NSC channel in MD cells. A putative role for
MD cell Ca2+ was considered early on in the study of TGF
signal generation (1).
Following contradictory reports
(26), the effects of changes
in [NaCl]L on MD [Ca2+]i have
recently been revisited (25).
It was convincingly demonstrated that MD
[Ca2+]i increased by
40 nM when
[NaCl]L was increased from 25 to 150 mM. In addition, this increase
was shown to be sensitive to basolateral application of 1 µM nifedipine. It
was suggested that the basolateral membrane depolarization that occurs with
elevated [NaCl]L
(13) opens or activates
voltage-dependent Ca2+ channels in the basolateral
membrane. Because a large concentration of nifedipine (1020 µM) did
not completely block the MD NSC channel, this casts some doubt on whether the
NSC channel is directly responsible for [NaCl]L-induced
Ca2+ influx across the basolateral membrane. It is
likely, however, that cell depolarization triggered by a rise in
[NaCl]L will increase the Po of the NSC
channels, which will further contribute to MD cell depolarization and help in
opening voltage-dependent Ca2+ channels. In the i/o
configuration, sensitivity of NSC channels to cytosolic
Ca2+ is not very high; >1 µM
Ca2+ is needed to activate the NSC channel. Because this
channel was observed to be functional in the c/a configuration, it appears
that the channel's Ca2+ sensitivity is much higher in
the presence of a normal cytosolic environment compared with the excised
configuration. It is possible that the NSC channel may in fact be sensitive to
small increases in [Ca2+]i that have been
observed when [NaCl]L is increased. Further experiments are needed
to check for the Ca2+ sensitivity of the cationic
channel in the c/a mode and to identify a specific inhibitor that could be
used to better define the role of this Ca2+-sensitive
channel in the physiology of MD cells.
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DISCLOSURES
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This work was supported by a Grant-in-Aid for International Scientific
Joint Research from the Ministry of Education, Science, Sports and Culture of
Japan (Y. Okada), the Kidney Foundation of Canada (J. Y. Lapointe), and
National Institute of Diabetes and Digestive and Kidney Diseases Grant
DK-32032 (P. D. Bell).
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ACKNOWLEDGMENTS
|
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The technical contribution of Bernadette Wallendorf is gratefully
acknowledged.
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FOOTNOTES
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Address for reprint requests and other correspondence: Y. Okada, National
Institute for Physiological Sciences, Myodaiji-cho, Okazaki 444-8585, Japan
(E-mail:
okada{at}nips.ac.jp).
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.
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