Correspondence to: Gerhard Giebisch, Department of Cellular & Molecular Physiology, Yale University School of Medicine, 333 Cedar Street, New Haven, CT 06520-8026. Fax:203-785-4951 E-mail:gerhard.giebisch{at}yale.edu.
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Abstract |
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We have used the patch-clamp technique to study the effects of changing extracellular ATP concentration on the activity of the small-conductance potassium channel (SK) on the apical membrane of the mouse cortical collecting duct. In cell-attached patches, the channel conductance and kinetics were similar to its rat homologue. Addition of ATP to the bathing solution of split-open single cortical collecting ducts inhibited SK activity. The inhibition of the channel by ATP was reversible, concentration dependent (Ki = 64 µM), and could be completely prevented by pretreatment with suramin, a specific purinergic receptor (P2) blocker. Ranking of the inhibitory potency of several nucleotides showed strong inhibition by ATP, UTP, and ATP--S, whereas
, ß-Me ATP, and 2-Mes ATP failed to affect channel activity. This nucleotide sensitivity is consistent with P2Y2 purinergic receptors mediating the inhibition of SK by ATP. Single channel analysis further demonstrated that the inhibitory effects of ATP could be elicited through activation of apical receptors. Moreover, the observation that fluoride mimicked the inhibitory action of ATP suggests the activation of G proteins during purinergic receptor stimulation. Channel inhibition by ATP was not affected by blocking phospholipase C and protein kinase C. However, whereas cAMP prevented channel blocking by ATP, blocking protein kinase A failed to abolish the inhibitory effects of ATP. The reduction of K channel activity by ATP could be prevented by okadaic acid, an inhibitor of protein phosphatases, and KT5823, an agent that blocks protein kinase G. Moreover, the effect of ATP was mimicked by cGMP and blocked by L-NAME (NG-nitro-L-arginine methyl ester). We conclude that the inhibitory effect of ATP on the apical K channel is mediated by stimulation of P2Y2 receptors and results from increasing dephosphorylation by enhancing PKG-sensitive phosphatase activity.
Key Words: K secretion, purinergic receptors, protein kinase A, phosphatase, protein kinase G
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INTRODUCTION |
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Principal cells of the cortical collecting ducts play a key role in the body's K homeostasis by controlling K secretion in the kidney. This process involves both active and passive processes, including active uptake of K in exchange for sodium by Na-K ATPase activity in the basolateral membrane, followed by passive diffusion along a favorable electrochemical gradient through K channels in the apical membrane (
Several studies have shown that purinergic receptors are located along the nephron, including the cortical collecting tubule (
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MATERIALS AND METHODS |
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Preparation of Mouse Cortical Collecting Duct
C57 mice and Sprague-Dawley rats were obtained from Charles River Laboratories and Taconic Farms, Inc. and kept on normal chow diet (PMI Nutrition International, Inc.) for 710 d before the experiments. Their weight varied between 20 and 25 g (mice) and 80 and 100 g (rats). The method for dissection of single mouse tubules was similar to that previously employed (
Patch-Clamp Technique
Borosilicate glass capillaries (Dagan Corp.) were used with a microelectrode puller (PP-83; Narishige Scientific Instrument Laboratory). The pipette resistance varied between 6 and 8 M when filled with 140 mM KCl. Single channel currents were recorded using an EPC-7 amplifier (List Electronics) and low-pass filtered at 1 kHz by an eight-pole Bessel filter (902 LPF; Frequency Devices, Inc.). Currents were digitized by an Axon Interface (Digidata 1200; Axon Instruments, Inc.) and transferred to a PC (E-3100; Gateway 2000). Data were analyzed using pCLAMP software (6.0.4; Axon Instruments, Inc.). If patches contained more than five channels, we used the NPo analysis program written by Dr. Junliang Sui from Mount Sinai Medical School (available at http://www.axon.com/pub/userware/popen) to calculate open probability. The effect of a particular agent was determined by observing the transition point where the channel open probability changed into a new steady state for at least 3060 s. The NPo was calculated as follows: NPo =
(t1 + t2 + ti) where ti is fractional open time spent at each of the observed current levels.
Solutions and Chemicals
Bath and dissection solutions were identical and contained (mM): 140 NaCl, 5 KCl, 1.8 MgCl2, 1.8 CaCl2, and 10 mM HEPES (pH 7.4 with NaOH). The pipette solution contained (mM): 140 KCl, 1.8 MgCl2, and 10 HEPES (pH 7.4 with KOH). Mg-ATP, adenosine 5'-0-3-thiotriphosphate (ATP--S), suramin, sodium fluoride, and indomethacin were purchased from Sigma Chemical Co., H7, H8, H9, H89, and U73122 from Alexis Biochemical Co., forskolin, calphostin C, okadaic acid, KT5823, L-NAME (NG-nitro-L-arginine methyl ester), 8-bromo-cGMP and 8-bromo-cAMP from Calbiochem Novabiochem Co., staurosporine from Boehringer-Mannheim, 2-methylthio ATP (2-Mes ATP), and
,ß-methylene ATP (
,ß-Me ATP) from Research Biochemicals Intl. All chemicals were prepared as stock solutions and added directly to the perfusion chamber to reach the desired final concentrations.
Statistics
Data are presented as mean value ± SEM. Paired Student's t test was used to perform statistical analysis and significance determined by P < 0.05.
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RESULTS |
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A representative recording of channel activity in a cell-attached patch of the apical membrane of a mouse CCD is shown in Fig 1 A. It is apparent that the channel has a high open probability (mean NPo = 0.92 ± 0.03, n = 7), similar to the value observed in the rat CCD (NPo = 0.93 ± 0.03, n = 3). Fig 1 B displays closed- and open-channel histograms, indicating a mean open time of 22.7 ms and a closed time of 1.4 ms. Note that long-lasting closed states can also be observed in the current trace. However, these events were too infrequent to allow appropriate curve fitting. Fig 1 C is a representative I-V curve yielding a value of 28.4 pS between -20 to +20 mV, a value also quite similar to that derived from data in the rat CCD (28.9 pS). These data are similar to those previously published (
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Fig 2 A shows single channel activity in which the effects of extracellular ATP were investigated. Addition of 100 µM ATP led to a sharp decline and blocked the channel by >90% within 3 min. NPo decreased by 92% ± 5.4 (n = 12). Channel inhibition was reversible (restored channel activity: NPo 98%). Calculation of the doseresponse curve yields a value of Ki of 64 µm (Fig 2 B). Recent studies in mammalian epithelia such as cells from mouse cortical collecting tubule have reported that elevation of extracellular ATP stimulated chloride secretion, but inhibited amiloride-sensitive sodium absorption (
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To assess the specificity of ATP-induced channel inhibition, we have examined the effects of several ATP analogs. Fig 3 summarizes these results. In cell-attached membrane patches, channel activity was sharply reduced by ATP (98%, n = 20), UTP (98%, n = 8), and ATP--S (90%, n = 6). In contrast, addition of
,ß-Me ATP and 2-Mes ATP failed to inhibit the channel activity significantly. The sequence of this nucleotide inhibitory potency is consistent with an effect of extracellular ATP on purinergic receptors of the P2Y2 type (
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The effects of suramin demonstrated in Fig 4 further support the involvement of purinergic receptors. Shown are the responses to ATP before and after addition of 100 µM suramin, a potent inhibitor of P2 receptors, to the bath solution. Channel inhibition by ATP is completely abolished by pretreatment of tubules with suramin for 5 min (control NPo: 2.76 ± 0.21; NPo after suramin + ATP: 2.76 ± 0.23, n = 6). These results show that the effects of ATP are dependent on purinergic receptors. They also exclude the possibility that inhibition of K channels could have occurred by direct passage of ATP across the cell membrane since the apical low-conductance K channel is inhibited by elevation of cytosolic ATP (
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Purinergic receptors have been reported on both apical and basolateral membranes of several epithelia (
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It has been reported that P2Y2 receptors can activate phospholipase C and reduce phosphatidylinositol 4,5-bisphosphate (PIP2) (
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Several previous studies have shown that stimulation of protein kinase C inhibits the native small-conductance K channel in the CCD and thick ascending limb (
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We further investigated the possibility that stimulation of P2Y2 receptors blocks the small-conductance K channel by decreasing the intracellular cAMP concentration. Such a mechanism is suggested by observations that extracellular ATP inhibits adenylate cyclase in renal LLC-PK1 cells through activation of P2 receptors (
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To test the possibility that the effect of ATP results from inhibition of PKA, we examined the effects of several blockers of PKA (H8, H89, and H9). Fig 9 summarizes the effects of H9, an inhibitor of PKA. H9 had no affect on channel activity before the addition of ATP to the bath solution, and it also fails to abolish the affect of ATP (control: NPo 12.8 ± 0.21; after ATP: NPo 0.02 ± 0.01, n = 6). Note that the membrane-permeable 8-bromo-cAMP now failed to relieve channel block by ATP, although it had been effective in the absence of the PKA inhibitor. Similar maneuvers were also observed with H8 (n = 6) and H89 (n = 4, data not shown), which means that the effect of ATP is not the result of inhibition of PKA. Rather, it suggests that enhanced dephosphorylation could be the mechanism of channel inhibition and that the effect of cAMP consists of antagonizing the inhibitory effect of phosphatases. This conclusion is based on observations that the activity of the native small-conductance K channel as well as that of the cloned ROMK channel depends both on the kinase-mediated phosphorylation of several serine and threonine sites on the channel, and on dephosphorylation by several membrane phosphatases (
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To test the possibility that an increase in phosphatase activity could mediate the inhibitory effect of ATP, experiments were carried out in the presence of a potent phosphatase inhibitor. Fig 10 shows an experiment in which the effects of okadaic acid were investigated. The ATP block is completely prevented by the inhibitor of phosphatase activity (okadaic acid: NPo 10.1 ± 0.21; after ATP: NPo 11.04 ± 0.29, n = 12). These results strongly support the view that activation of phosphatases mediates the effects of extracellular ATP on the small-conductance K channel.
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Previous studies from our laboratory had shown that several phosphatases, including PP2A and PP2C, participate in the regulation of both the native K channel in principal cells (
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Finally, the role of cGMP in modulating the inhibitory effect of extracellular ATP was directly demonstrated in experiments in which exposure to membrane-permeant cGMP (100 µM) mimicked the effects of ATP (Fig 12 A). Fig 12 B summarizes results of 17 experiments showing that channel activity reversibly decreased by cGMP to 20% ± 8.7 of the control value. Furthermore, an important role of NO is suggested by our observations that pretreatment of the tubule for 20 min with 100 µM L-NAME, an inhibitor of NOS, abolished the inhibitory effect of ATP (Fig 12 B).
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Fig 13 provides the summary of various maneuvers designed to test the effect of several agents known to modulate small-conductance K channel activity. Since suramin, an inhibitor of P2, abolished the inhibitory effect of ATP and pretreatment of the tubules with cAMP, okadaic acid, and KT 5823 prevented the ATP inhibition on channel activity, it is strongly suggested that the effect of extracellular ATP was involved in channel phosphorylation and dephosphorylation processes.
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DISCUSSION |
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The main finding of the present study is that extracellular ATP inhibits apical small-conductance K channels in principal tubule cells by mechanisms involving purinergic receptor activation and changes in channel dephosphorylation. The finding that purinergic receptors are present in the nephron (
Previous studies on excised membrane patches have shown that millimolar concentrations of ATP in the cytosolic medium inhibit the small-conductance K channel (
Purinergic receptors have been identified in numerous cells including renal epithelium (
P2 receptors couple to several signaling pathways and their activation has been shown to modulate the activity of phospholipase C (
Fig 14 shows a membrane model including the main factors proposed to mediate the effects of ATP. Shown is the cAMP-dependent pathway responsible for channel phosphorylation and the dephosphorylation pathway acting through the phosphatases such as PP2A and PP2C, both of which have been identified in apical membrane patches of principal cells (
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Distinct effects of extracellular ATP on sodium chloride transport were reported in cultured kidney cells of cortical collecting tubules (
One uncertainty concerns the concentration of ATP in the tubule fluid since no measurements are available under free-flow conditions in either native or perfused tubules in either physiological or pathophysiological conditions. Information is presently limited to tubule cells in culture in which the range of extracellular ATP varied between 0.5 and 10 µM (
The physiological role of extracellular ATP in the regulation of tubule function, especially with respect to the process of distal potassium secretion, is incompletely understood. Extracellular ATP signaling has been implicated in several epithelial transport processes, for instance in the control of cell volume during exposure to hypotonic media (
In conclusion, we have observed that ATP has significant inhibitory actions on secretory K channels in principal cells of the mouse cortical collecting tubule. These effects can be shown to be mediated by purinergic P2Y2 receptors and are best explained by activation of membrane-bound phosphatases through a cGMP-dependent pathway. It is possible that local release of ATP, through its luminal actions on the small-conductance K channel in the apical membrane of principal cells, plays a role in autocrine or paracrine regulation of K secretion.
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Footnotes |
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1 Abbreviation used in this paper: CCD, cortical collecting duct.
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Acknowledgements |
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This work was supported by an interactive research grant (DK 54998) from the National Institutes of Health (NIH). Dr. MacGregor is supported by the National Kidney Foundation. Dr. W.H. Wang is supported by NIH grant DK 47402.
Submitted: 1 March 2000
Revised: 15 June 2000
Accepted: 15 June 2000
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