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1 Institut de Pharmacologie Moléculaire et Cellulaire, CNRS UMR 6097, 660 route des Lucioles, Sophia Antipolis, 06560 Vabonne, France
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(Received 5 July 2004;
accepted after revision 21 October 2004;
first published online 28 October 2004)
Corresponding author M. Lazdunski: Institut de Pharmacologie Moléculaire et Cellulaire, CNRS UMR 6097, 660 route des Lucioles, Sophia Antipolis, 06560 Vabonne, France. Email: ipmc{at}ipmc.cnrs.fr
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Introduction |
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gO2). These ROS are generated by various metabolic pathways, and a disruption of the fine balance between their generation and their elimination can lead to pathophysiological states. This work shows that TALK-1, and TALK-2 are very specifically expressed in the exocrine pancreas and that these K2P channels are highly modulated both by NOS and ROS.
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Solutions
A rose bengal (Sigma) stock solution was made daily in ND96 saline solution at concentration of 1 mM and kept at –20°C in darkness because of strong decay of the dye in light. Similarly, Angeli's salt stock solution (100 mM in NaOH 0.1 M) was made daily. Dilutions of rose bengal (1 µM) and Angeli's salt (1 mM) solutions were renewed prior to each experiment and kept in darkness after pH adjustment. tert-Butyl hydroperoxide (tBHP) solutions were made daily from a 70% (w/v) commercial solution (Sigma). Stock solutions of xanthine (50 mM) and xanthine oxidase (50 mU ml–1) were prepared and kept at +5°C and –20°C, respectively. Solutions of 3-morpholinosydnonimine (SIN-1, 1 mM), 8-(4-chlorophenylthio)-guanosine 3':5'-cyclic monophosphate (CPT-GMPc, 500 µM), sodium nitroprussiate (SNP, 1 mM) and dithiothreitol (DTT, 2 mM) were made daily in saline solution. The SNP and DTT mixture was freshly made every two hours.
Electrophysiological measurements in Xenopus oocytes
Xenopus laevis oocytes were used, as previously described (Reyes et al. 1998), after being surgically removed from animals anaesthetized on ice and then killed humanely by decapitation. Oocytes were injected with either 16, 16, 4, and 4 ng RNA (hTALK-1, hTALK-2, hTASK-1, and hTASK-2, respectively). The standard solution (ND96) contained (mM): 96 NaCl, 2 KCl, 1.8 CaCl2, 2 MgCl2 and 5 Hepes (pH adjusted to 7.4 with NaOH). The experimental chamber was illuminated with a broad-band white light (150 W) equipped with optic fibres that delivered 
1200 lux at 533 ± 10 nm. The data were considered as statistically different for P-values lower than 0.05.
In situ hybridization in human pancreas
The following primers (TALK1: sense: 5'-ATCACTCT-CAGCACCATTGGC-3'; antisense: 5'-AGTGGAGGAAG-CGTCTAG-3'; TALK2: sense: 5'-TACTCGAGTTATAC-TCCATTCTTTGGTCG-3'; antisense: 5'-TAGAATTCTC-GGGTGATATTCCGTTTGTT-3') were used to amplify, by PCR, regions corresponding to the 3' UTR of TALK-1 and TALK-2. Human pancreas cDNA (Clontech) was used as the template. The PCR products were then subcloned into pBluescript SK-plasmid and sequenced. Specific antisense cRNA probes were generated with T7-RNA polymerase (Roche Diagnostics), by in vitro transcription using fluorescein-UTP, from XbaI-linearized pBluescript SK-plasmid, whereas sense riboprobes used for control experiments were produced with the SP6-RNA polymerase from the same EcoRI-linearized plasmid.
In situ hybridization experiments were performed on adult human pancreas paraffin-embedded slices purchased from BioChain (Hayward, CA, USA). Sections were incubated for 30 min at 60°C and dewaxed twice for 10 min in fresh xylene and then rehydrated. Sections were then fixed in ice-cold 4% (w/v) paraformal-dehyde/0.1 M sodium phosphate buffer solution (PBS, pH 7.4) for 10 min, permeabilized for 10 min in ice-cold 0.1% Triton in PBS, and rinsed three times in PBS. The sections were prehybridized for 10 min at 37°C in 4 x SSC and 50% formamide, and hybridized overnight at 72°C in 4 x SSC, 50% formamide, 2.5x Denhardt's solution, 250 µg ml–1 herring sperm DNA, 125 µg ml–1 yeast tRNA, and 10 ng fluorescein-labelled probe. Fluorescein-labelled probes were detected according to the protocol from Roche Diagnostics. Briefly, the sections were incubated with antifluorescein-alkaline phosphatase for 2 h at room temperature, rinsed with 1 x washing buffer, and incubated with nitroblue tetrazolium (NTB)–5-bromo-4-chloro-3-indolyl-phosphate (BCIP) for 30 min in the dark.
TASK-2 promoter-driven X-gal staining in mouse pancreas
Dr W. C. Skarnes (University of California, Berkeley, Berkeley, CA, USA) provided the genetically modified mice used in this work. TASK-2 knockout (KO) mice were generated by gene-trap insertion of Lac Z gene as previously described (Skarnes, 2000). The TASK-2 promoter-driven X-Gal staining was visualized by ß-galactosidase histochemistry. The mice were anaesthetized using CO2 and then killed humanely by decapitation. Pancreas from wild-type and TASK-2 KO mice were harvested and fixed in 2% paraformaldehyde in PBS for 5 min at room temperature. After rinsing, 16 µm sections were obtained using a vibratome. Floating sections were stained overnight at 37°C in the following mixture: 20 mM TRIS pH 7.4, 0.01% Na deoxycholate, 0.02% Nonidet P-40 (Ipegal, Sigma), 10 mM sodium phosphate, 1 mg ml–1 X-gal (5-bromo-4-chloro-3-indolyl-D-galactoside), 5 mM potassium ferricyanide, 5 mM potassium ferrocyanide, and 2 mM MgCl2. The slices were then counterstained with haematoxylin and eosin.
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Control in situ hybridization experiments performed on paraffin-embedded sections of human pancreas with sense riboprobes for TALK-1 and TALK-2 show a weak background (Fig. 2A–B). Experiments performed with antisense riboprobes revealed that expression of TALK-1 and TALK-2 is strong in the exocrine pancreas (Fig. 2D, E,G–H), much higher than the background signal, while none of these channels are expressed in the endocrine pancreas (Fig. 2). Thus TALK-1 expression is not only restricted to a unique organ, the pancreas (Decher et al. 2001; Girard et al. 2001), it is also restricted to exocrine cells. This is the first example of such a restrictive expression of a K2P channel.
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The localization of TASK-2, a close relative of TALK-1 and TALK-2 (Fig. 1A), was then performed. The targeting vector used in the laboratory of W. Skarnes for the generation of TASK-2 KO mice contained a ß-galactosidase gene, LacZ. Thus, ß-galactosidase gene expression is controlled by the TASK-2 promoter in the KO mice (Skarnes, 2000). The tissue localization of TASK-2 using the X-gal staining method on the same mice was previously described for the kidney (Warth et al. 2004). The TASK-2 promoter-driven X-gal staining was observed in the pancreas, it is much higher than the background signal observed in wild-type mice (Fig. 2C). TASK-2 is situated in the islets of Langherans as well as in acinar cells (Fig. 2F–I). Moreover, the dual localization of TASK-2 in the exocrine pancreas and the islets of Langherans is fully confirmed by immunohistochemistry experiments using a specific antibody against the TASK-2 protein (personal communication from Dr Richard Warth).
Effects of NOS donors on K2P channels expressed in oocytes
The effects of four different NOS donors were tested on three pancreatic K2P channels (TALK-1, TALK-2, TASK-2) expressed in Xenopus laevis oocytes. Only variations greater than 10% of the recorded current at +50 mV were considered as a real effect on the expressed channel and not an artefact due to the various endogenous conductances present in oocytes (Dascal, 1987).
The first NOS donor tested was the widely used 3-morpholinosydnonimine (SIN-1, 1 mM). SIN-1 produces nitric oxide radicals (NO·) and superoxide ions (·O2–) which react together leading to peroxynitrite (OONO–) (Beckman & Koppenol, 1996). A low level of inhibition was found for all channels (Fig. 3A). The second NOS donor used was Angeli's salt (1 mM) which mainly produces the nitroxyl anion NO– (Hughes & Cammack, 1999). None of the tested K2P-expressing oocytes were significantly sensitive to this compound (Fig. 3B). The third NOS donor was sodium nitroprussiate (SNP, 1 mM) which mainly produces the nitrosonium cation NO+ (Hughes, 1999). There was no significant effect of this compound on the tested channels (Fig. 3C). The fourth NOS donor assayed on K2P channels was the mixture of SNP (1 mM) plus the reducing agent dithiothreitol (DTT, 2 mM) which mainly produces the nitric oxide radical NO· (Bates et al. 1991). We found a slight inhibition of the TASK-2 current, a small activation of TALK-1 and a very large activation of the closely related TALK-2 channel (Fig. 3D). For TALK-2 we recorded an average current of 1.0 ± 0.1 µA (n = 14) at +50 mV which increased to 5.6 ± 1.3 µA (n = 14) in the presence of the SNP/DTT mixture. This drastic effect was observed in 70% of the tested oocytes. If the non-responding oocytes were excluded, the average increase elicited by SNP/DTT was huge, i.e. 1018 ± 234% (n = 9). This activation of TALK-2 was observed at all potentials (Fig. 3E). Current kinetics were not significantly modified with activation rates of 140.4 ± 7.5 ms (n = 7) and 134.1 ± 21.3 ms (n = 4) in control and SNP/DTT-treated oocytes, respectively (Student's t test, P = 0.003).
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Effects of ROS donors on K2P channels expressed in oocytes
As for NOS donors, the effects of four different ROS donors were tested on the different clones of K2P channels expressed in Xenopus laevis oocytes.
First assayed was the commonly used superoxide ion (·O2–) -generating mixture, xanthine (50 µM) plus xanthine oxidase (50 mU ml–1). TASK-2 and TALK-2 currents measured at +50 mV were strongly activated by this mixture (+ 93.1 ± 4.3%, n = 13, and +135.9 ± 16.5%, n = 6, respectively). A weak activation of TALK-1 (less than 7%) was observed (Fig. 4A). The activation of TALK-2 was observed at all potentials with no modification of the current kinetics (Fig. 4B and C). In some cases the xanthine/xanthine oxidase mixture induced a small transient endogenous current which slightly shifted the observed current and could be observed as a small tail current following the voltage steps (not shown). The stimulation of TASK-2 was clearly observed at all potentials and the activation rate in control, 140.4 ± 7.5 ms (n = 7), was significantly slower after perfusion of the ROS donor (112.7 ± 13.0 ms, n = 4, Student's t test, P = 0.003) (Fig. 4D and E).
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gO2) following photoactivation. After photoactivation, a weak inhibition of TASK-2, a large increase of TALK-1, +442.3 ± 17.7% (n = 18), and a huge increase of TALK-2 activity, +819.0 ± 36.3% (n = 8), were observed (Fig. 5A). Again the effects depended on the channel type, and pairs of closely related channels presented different sensitivities (TALK-1/TALK-2). The activation of TALK channels was observed at all potentials giving rise to large inward and outward currents (Fig. 5B and D). TALK current kinetics were not modified by photoactivated rose bengal (Fig. 5C and E). We then confirmed that the effect was due to ROS by performing photoactivation of rose bengal under hypoxic conditions using pure nitrogen bubbling. Indeed the activation observed with TALK-1 and TALK-2 was dramatically reduced by nitrogen bubbling with activations of +226.4 ± 13.2% (n = 9) and +251.2 ± 10.8% (n = 5), respectively. When perfused in darkness, none of the recorded K2P currents, except TALK-2, were sensitive to rose bengal 1 µM (not shown). This sensitivity of TALK-2 in darkness is probably an artefact due to the difficulty of working in complete darkness and the high sensitivity of this K2P channel to photoactivation (see below). A solution photoactivated for 15 h, hence depleted of its ability to generate singlet oxygen, was used to test this point. This solution was not active on TALK-2 current, showing that a direct effect of rose bengal on TALK-2 is excluded and that the small activation in relative darkness was indeed an artefact (not shown).
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Discussion |
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A background conductance previously recorded in acinar cells has a conductance of 48 pS, is inhibited by intracellular acidification and is resistant to TEA and insensitive to 4-aminopyridine (4-AP) (Schmid et al. 1997). These properties resemble those previously described for TALK channels (Girard et al. 2001; Kang & Kim, 2004). In situ hybridization experiments clearly show that TALK-1 and TALK-2 transcripts are exclusively and specifically present in acinar cells.
Effects of NOS donors on pancreatic K2P channels
The nerve-mediated control of exocrine pancreatic secretion presents a positive regulation by nitric oxide (Wrenn et al. 1994). The mechanisms underlying the observed effects are unknown, but considering that nitric oxide strongly activates both TALK-1 and TALK-2 channels, these two channels might well be involved in the NO-dependent stimulation of secretion. The strong activation of TALK-2 by nitric oxide is very interesting because the basal K+ current generated by this channel is low at physiological pH. Nitric oxide could then work as an endogenous ligand needed to switch on the TALK-2 current. Since specific inhibitors for TALK-1 and TALK-2 have not yet been discovered, the hypothesis of a role for TALK channels in the NO-activation of secretion will require exploration of TALK gene-deleted mice to be conclusively demonstrated. Our study shows that NOS are mostly active on TALK-2 which is also expressed in the heart (Girard et al. 2001). A role for NOS is suggested in preconditioning (Miller, 2001) and thus TALK-2 could also be implicated in this phenomenon.
Effects of ROS donors on pancreatic K2P channels
ROS such as superoxide ion (·O2–), hydrogen peroxide (H2O2), hydroxyl radical (·OH), and singlet oxygen (1gO2) are produced as by-products of oxidative metabolism. ROS production is enhanced in many pathophysiological states such as apoptosis (for review see Simon et al. 2000) and more specifically, in relation to this study, they are produced in acute pancreatitis (for review see Schulz et al. 1999). The most striking effect of ROS is the strong activation of TALK-1 and TALK-2 by singlet oxygen produced upon photoactivation of rose bengal. Superoxide, the most commonly described ROS, activates TALK-2 (and TASK-2) but not TALK-1. The very high levels of activation seen for TALK-2 are particularly interesting since TALK-2, as previously indicated, is almost silent at rest (see Fig. 1B and Girard et al. 2001). Therefore, ROS, just like NO, could also act as endogenous openers of this particular channel and be important during normal physiological function. An excess in ROS production would produce an enormous activation of the pancreatic K2P channels and might then induce secretion dysfunction and apoptosis. It has recently been demonstrated that although TASK channels are important for neuronal function (Talley et al. 2000), excess expression of TASK channels in neuronal cells will lead to apoptosis (Lauritzen et al. 2003) that might be essential in cerebellum development. K2P channels, when overexpressed, can behave as apoptotic channels. It is worth noting that a high production of NOS has also been reported in acute pancreatitis (for review see Schulz et al. 1999). A synergy of NOS and ROS activation of K2P channels is possible in disease states associated with the pancreatic exocrine system.
In conclusion, this work indicates the presence of TALK channels in the exocrine pancreas and suggests that they might be implicated in the control of secretion. It also shows that both ROS and NOS can trigger impressive activation of these channels, suggesting that both ROS and NOS could act as endogenous openers. Depending on the generated species and the quantities produced, NOS could regulate the normal secretory process (Konturek et al. 1994; Molero et al. 1995) and in pathological states both ROS (Dabrowski et al. 1999; Schulz et al. 1999) and NOS (Konturek et al. 1994; Molero et al. 1995) could be associated with pancreatitis. The development of drugs acting specifically on these channels might then be useful for the treatment of exocrine pancreatic diseases.
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References |
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