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


    ABSTRACT
 TOP
 ABSTRACT
 MATERIALS AND METHODS
 RESULTS
 DISCUSSION
 REFERENCES
 
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.


    MATERIALS AND METHODS
 TOP
 ABSTRACT
 MATERIALS AND METHODS
 RESULTS
 DISCUSSION
 REFERENCES
 
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 15–20 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.


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Table 1. Solution composition

 

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{Omega} .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.


    RESULTS
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 ABSTRACT
 MATERIALS AND METHODS
 RESULTS
 DISCUSSION
 REFERENCES
 
During patch clamp of the lateral membranes of MD cells, several different channels were identified, including small (10–25 pS) and intermediate conductance levels (30–50 pS) as well as a maxi-Cl channel (~380 pS) (3). In the present study, we will specifically deal with a small-conductance channel (20–23 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.

 

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.



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Fig. 2. Average inside-out (i/o) patch I-V curves in the presence of 140 mM KCl in the pipette. The effects of changes in the bath solution (cytosolic surface of the patch) from Ringer (n = 8; 135 mM Na++5 mM K+, {blacksquare}) to a low-Na+ solution (n = 5; 13.5 mM Na++5 mM K+, {circ}) or to a high-K+ solution (n = 6; 80 mM K++30 mM Na+, {square}) on the average I-V relationship are shown.

 

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).

 

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 (1–3). 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.

 


    DISCUSSION
 TOP
 ABSTRACT
 MATERIALS AND METHODS
 RESULTS
 DISCUSSION
 REFERENCES
 
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 20–23 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 (10–20 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.


    DISCLOSURES
 
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).


    ACKNOWLEDGMENTS
 
The technical contribution of Bernadette Wallendorf is gratefully acknowledged.


    FOOTNOTES
 

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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 ABSTRACT
 MATERIALS AND METHODS
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 DISCUSSION
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00313.2002v1
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