{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,3,14]],"date-time":"2026-03-14T03:43:42Z","timestamp":1773459822869,"version":"3.50.1"},"reference-count":56,"publisher":"Wiley","issue":"3","license":[{"start":{"date-parts":[[2005,2,4]],"date-time":"2005-02-04T00:00:00Z","timestamp":1107475200000},"content-version":"vor","delay-in-days":3718,"URL":"http:\/\/onlinelibrary.wiley.com\/termsAndConditions#vor"}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["Journal Cellular Physiology"],"published-print":{"date-parts":[[1994,12]]},"abstract":"<jats:title>Abstract<\/jats:title><jats:p>The tissue distribution of P\u2010glycoprotein (Pgp) and the structurally related cystic fibrosis transmembrane conductance regulator (CFTR) is apparently mutually exclusive, particularly in epithelia; where one protein is expressed the other is not. To study the possible function(s) of Pgp and its potential effects on CFTR expression in epithelia, HT\u201029 colon adenocarcinoma cells, which constitutively express CFTR, were pharmacologically adapted to express the classical multidrug resistance (MDR) phenotype (Pgp<jats:sup>+<\/jats:sup>). Concomitant with the appearance of Pgp and MDR phenotype (drug resistance, reduced drug accumulation and increased drug efflux), CFTR levels and cAMP\u2010stimulated Cl conductances were markedly decreased compared to wild\u2010type HT\u201029 (Pgp<jats:sup>\u2212<\/jats:sup>) cells (as shown using the whole cell patch clamp technique). Removal of drug pressure led to the gradual decrease in Pgp levels and MDR phenotype, as evidenced by increased rhodamine 123 accumulation (Pgp\u2010Rev). Concomitantly, CFTR levels and cAMP\u2010stimulated Cl<jats:sup>\u2212<\/jats:sup> conductances incresed. The cell responses of Pgp\/Rev cells were heterogeneous with respect to both Pgp and CFTR functions. We also studied the possible contribution of Pgp to hypotonically activated (HCS) ion conductances. K<jats:sup>+<\/jats:sup> and Cl<jats:sup>\u2212<\/jats:sup> effluxes from Pgp<jats:sup>\u2212<\/jats:sup> cells were markedly increased by HCS. This increase was twice as high as that induced by the cation ionophore gramicidin; it was blocked by the Cl<jats:sup>\u2212<\/jats:sup> channel blocker DIDS (4,4\u2032\u2010disothiocyano\u20102,2\u2032\u2010disulfonic stilbene) and required extracellular Ca<jats:sup>2+<\/jats:sup>. In Pgp<jats:sup>+<\/jats:sup> cells, the HCS\u2010induced fluxes were not significantly different from those of Pgp<jats:sup>\u2212<\/jats:sup> cells. Verapamil (10 \u03bcM), which caused 80% reversal of Pgp\u2010associated drug extrusion, failed to inhibit the HCS\u2010evoked Cl<jats:sup>\u2212<\/jats:sup> efflux of Pgp<jats:sup>+<\/jats:sup> cells. Similarly, HCS increased Cl<jats:sup>\u2212<\/jats:sup> conductance to the same extent in Pgp<jats:sup>\u2212<\/jats:sup>, Pgp<jats:sup>+<\/jats:sup> and Pgp\u2010Rev cells. Verapamil (100 \u03bcM), but not 1,9\u2010dideoxyforskolin (50 and 100 \u03bcM), partially inhibited the HCS\u2010evoked whole cell current (WCC) in all three lines. Since the inhibition by verapamil was not detected in the presence of the K<jats:sup>+<\/jats:sup> channel blocker Ba<jats:sup>2+<\/jats:sup> (3 mM), it is suggested that verapamil affects K<jats:sup>+<\/jats:sup> and not Cl<jats:sup>\u2212<\/jats:sup> conductance. We conclude that hypotonically activated Cl<jats:sup>\u2212<\/jats:sup> and K<jats:sup>+<\/jats:sup> conductances are similar in HT\u201029 cells irrespective of Pgp expression. Expression of high levels of Pgp in HT\u201029 cells confers no physiologically significant capacity for cell volume regulation. \u00a9 1994 Wiley\u2010Liss, Inc.<\/jats:p>","DOI":"10.1002\/jcp.1041610302","type":"journal-article","created":{"date-parts":[[2005,2,26]],"date-time":"2005-02-26T04:01:27Z","timestamp":1109390487000},"page":"393-406","source":"Crossref","is-referenced-by-count":37,"title":["Effects of P\u2010glycoprotein expression on cyclic AMP and volume\u2010activated ion fluxes and conductances in HT\u201029 colon adenocarcinoma cells"],"prefix":"10.1002","volume":"161","author":[{"given":"K.","family":"Kunzelmann","sequence":"first","affiliation":[]},{"given":"I. N.","family":"Slotki","sequence":"additional","affiliation":[]},{"given":"P.","family":"Klein","sequence":"additional","affiliation":[]},{"given":"T.","family":"Koslowsky","sequence":"additional","affiliation":[]},{"given":"D. A.","family":"Ausiello","sequence":"additional","affiliation":[]},{"given":"R.","family":"Greger","sequence":"additional","affiliation":[]},{"given":"Z. I.","family":"Cabantchik","sequence":"additional","affiliation":[]}],"member":"311","published-online":{"date-parts":[[2005,2,4]]},"reference":[{"key":"e_1_2_1_2_1","doi-asserted-by":"publisher","DOI":"10.1126\/science.1712984"},{"key":"e_1_2_1_3_1","doi-asserted-by":"publisher","DOI":"10.1016\/0092-8674(91)90072-7"},{"key":"e_1_2_1_4_1","doi-asserted-by":"publisher","DOI":"10.1073\/pnas.85.12.4350"},{"key":"e_1_2_1_5_1","doi-asserted-by":"publisher","DOI":"10.1002\/mrd.1080250202"},{"key":"e_1_2_1_6_1","doi-asserted-by":"publisher","DOI":"10.1016\/0092-8674(92)90155-6"},{"key":"e_1_2_1_7_1","doi-asserted-by":"publisher","DOI":"10.1111\/j.1432-1033.1992.tb16911.x"},{"key":"e_1_2_1_8_1","doi-asserted-by":"crossref","first-page":"10465","DOI":"10.1016\/S0021-9258(19)50041-2","article-title":"Induction of expression of the cystic fibrosis transmembrane conductance regulator","volume":"267","author":"Breuer W.","year":"1992","journal-title":"J. Biol. Chem."},{"key":"e_1_2_1_9_1","doi-asserted-by":"crossref","first-page":"13935","DOI":"10.1016\/S0021-9258(19)85192-X","article-title":"Protein kinase C mediates down\u2010regulation of cystic fibrosis transmembrane conductance regulator levels in epithelial cells","volume":"268","author":"Breuer W.","year":"1993","journal-title":"J. Biol. Chem."},{"key":"e_1_2_1_10_1","doi-asserted-by":"publisher","DOI":"10.1152\/ajpcell.1993.265.6.C1711"},{"key":"e_1_2_1_11_1","doi-asserted-by":"publisher","DOI":"10.1016\/0092-8674(91)90446-6"},{"key":"e_1_2_1_12_1","doi-asserted-by":"publisher","DOI":"10.1073\/pnas.88.20.9262"},{"key":"e_1_2_1_13_1","first-page":"161","article-title":"A model for computer simulation of P\u2010glycoprotein and transmembrane delta pH mediated anthracycline transport in multidrug resistant tumor cells","volume":"1109","author":"Demant E. J.","year":"1990","journal-title":"Biochim. Biophys. Acta"},{"key":"e_1_2_1_14_1","doi-asserted-by":"publisher","DOI":"10.1146\/annurev.bi.58.070189.001033"},{"key":"e_1_2_1_15_1","doi-asserted-by":"publisher","DOI":"10.1007\/978-1-4757-1647-4_5"},{"key":"e_1_2_1_16_1","first-page":"156","article-title":"Pharmacology of drugs that alter multidrug resistance in cancer","volume":"42","author":"Ford J. M.","year":"1990","journal-title":"Pharmacol. Rev."},{"key":"e_1_2_1_17_1","doi-asserted-by":"publisher","DOI":"10.1016\/0006-291X(91)91692-6"},{"key":"e_1_2_1_18_1","doi-asserted-by":"publisher","DOI":"10.1016\/0092-8674(92)90263-C"},{"key":"e_1_2_1_19_1","doi-asserted-by":"publisher","DOI":"10.1016\/0165-6147(88)90117-4"},{"key":"e_1_2_1_20_1","doi-asserted-by":"publisher","DOI":"10.1016\/S0021-9258(18)37730-5"},{"key":"e_1_2_1_21_1","first-page":"84","volume-title":"Basic Principles in Transport. Comp. Physiol.","author":"Greger R.","year":"1989"},{"key":"e_1_2_1_22_1","doi-asserted-by":"publisher","DOI":"10.1038\/360759a0"},{"key":"e_1_2_1_23_1","first-page":"283","article-title":"Plasma and mitochondrial transmembrane potentials in adriamycin resistant and sensitive Friend leukemia cells as determined by flow cytometry","volume":"28","author":"Hasmann M.","year":"1987","journal-title":"Proc. Am. Assoc. Cancer Res."},{"key":"e_1_2_1_24_1","doi-asserted-by":"publisher","DOI":"10.1152\/ajpcell.1992.262.5.C1161"},{"key":"e_1_2_1_25_1","doi-asserted-by":"publisher","DOI":"10.1152\/physrev.1989.69.2.315"},{"key":"e_1_2_1_26_1","doi-asserted-by":"publisher","DOI":"10.1016\/S0021-9258(20)80566-3"},{"key":"e_1_2_1_27_1","doi-asserted-by":"publisher","DOI":"10.1038\/346362a0"},{"key":"e_1_2_1_28_1","doi-asserted-by":"crossref","first-page":"11693","DOI":"10.1016\/S0021-9258(18)80120-X","article-title":"The function of GP\u2010170, the multidrug resistance gene product, in rat liver canalicular membrane vesicles","volume":"264","author":"Kamimoto Y.","year":"1989","journal-title":"J. Biol. Chem."},{"key":"e_1_2_1_29_1","doi-asserted-by":"publisher","DOI":"10.1093\/jnci\/81.9.706"},{"key":"e_1_2_1_30_1","doi-asserted-by":"publisher","DOI":"10.1016\/0092-8674(91)90498-N"},{"key":"e_1_2_1_31_1","first-page":"3025","article-title":"Possible link between the intrinsic drug resistance of colon tumors and a detoxification mechanism of intestinal cells","volume":"48","author":"Klohs W. D.","year":"1988","journal-title":"Cancer Res."},{"key":"e_1_2_1_32_1","doi-asserted-by":"publisher","DOI":"10.1007\/BF00370255"},{"key":"e_1_2_1_33_1","doi-asserted-by":"publisher","DOI":"10.1007\/BF00374832"},{"key":"e_1_2_1_34_1","doi-asserted-by":"publisher","DOI":"10.1007\/BF00374833"},{"key":"e_1_2_1_35_1","doi-asserted-by":"publisher","DOI":"10.1016\/0006-291X(89)91988-8"},{"key":"e_1_2_1_36_1","doi-asserted-by":"publisher","DOI":"10.1007\/978-1-4615-7858-1_7"},{"key":"e_1_2_1_37_1","doi-asserted-by":"publisher","DOI":"10.1152\/physrev.1992.72.4.1037"},{"key":"e_1_2_1_38_1","first-page":"305","article-title":"Specific inhibitors distinguish the chloride channel and drug transporter functions associated with the multidrug resistance P\u2010glycoprotein","volume":"1","author":"Mintenig G. M.","year":"1993","journal-title":"Receptors and Channels"},{"key":"e_1_2_1_39_1","doi-asserted-by":"publisher","DOI":"10.1016\/0925-4439(92)90131-6"},{"key":"e_1_2_1_40_1","doi-asserted-by":"publisher","DOI":"10.1146\/annurev.ph.52.030190.000331"},{"key":"e_1_2_1_41_1","doi-asserted-by":"publisher","DOI":"10.1096\/fasebj.4.10.2197151"},{"key":"e_1_2_1_42_1","doi-asserted-by":"publisher","DOI":"10.1126\/science.2475911"},{"key":"e_1_2_1_43_1","first-page":"307","volume-title":"Progress in Cell Research","author":"Rothstein A.","year":"1992"},{"key":"e_1_2_1_44_1","doi-asserted-by":"publisher","DOI":"10.1093\/jnci\/78.1.171"},{"key":"e_1_2_1_45_1","first-page":"840","article-title":"Transport of digoxin by human P\u2010glycoprotein expressed in a porcine kidney epithelial cell line","volume":"263","author":"Tangiwara Y.","year":"1992","journal-title":"J. Pharmacol. Exp. Ther."},{"key":"e_1_2_1_46_1","first-page":"5544","article-title":"Cross\u2010resistance to rhodamine 123 in adriamycin\u2010 and daunorubicin\u2010resistant Friend leukemia cell variants","volume":"44","author":"Tapiero H.","year":"1984","journal-title":"Cancer Res."},{"key":"e_1_2_1_47_1","doi-asserted-by":"publisher","DOI":"10.1073\/pnas.84.21.7735"},{"key":"e_1_2_1_48_1","doi-asserted-by":"publisher","DOI":"10.1177\/37.2.2463300"},{"key":"e_1_2_1_49_1","doi-asserted-by":"publisher","DOI":"10.1038\/356057a0"},{"key":"e_1_2_1_50_1","doi-asserted-by":"publisher","DOI":"10.1007\/BF00370571"},{"key":"e_1_2_1_51_1","doi-asserted-by":"crossref","first-page":"10319","DOI":"10.1016\/S0021-9258(18)99228-8","article-title":"Down\u2010regulation of cystic fibrosis gene mRNA transcript levels and induction of the cystic fibrosis chloride secretory phenotype in epithelial cells by phorbol ester","volume":"266","author":"Trapnell B. C.","year":"1991","journal-title":"J. Biol. Chem."},{"key":"e_1_2_1_52_1","doi-asserted-by":"publisher","DOI":"10.1038\/353434a0"},{"key":"e_1_2_1_53_1","doi-asserted-by":"publisher","DOI":"10.1002\/j.1460-2075.1992.tb05528.x"},{"key":"e_1_2_1_54_1","doi-asserted-by":"publisher","DOI":"10.1038\/355830a0"},{"key":"e_1_2_1_55_1","first-page":"163","article-title":"Correction of altered plasma membrane potentials. A possible mechanism of cyclosporin A and verapamil reversal of pleiotropic drug resistance in neoplasia","volume":"22","author":"Vayuvegla B.","year":"1988","journal-title":"Cancer Chemother. Pharmacol."},{"key":"e_1_2_1_56_1","first-page":"539","article-title":"Partial reversal of multidrug resistance by forskolin and 1,9\u2010dideoxyforskolin in murine sarcoma S180 variants","volume":"48","author":"Wadler S.","year":"1988","journal-title":"Cancer Res."},{"key":"e_1_2_1_57_1","doi-asserted-by":"publisher","DOI":"10.1016\/0896-6273(92)90196-K"}],"container-title":["Journal of Cellular Physiology"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/api.wiley.com\/onlinelibrary\/tdm\/v1\/articles\/10.1002%2Fjcp.1041610302","content-type":"unspecified","content-version":"vor","intended-application":"text-mining"},{"URL":"https:\/\/onlinelibrary.wiley.com\/doi\/pdf\/10.1002\/jcp.1041610302","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2023,10,24]],"date-time":"2023-10-24T05:00:35Z","timestamp":1698123635000},"score":1,"resource":{"primary":{"URL":"https:\/\/onlinelibrary.wiley.com\/doi\/10.1002\/jcp.1041610302"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[1994,12]]},"references-count":56,"journal-issue":{"issue":"3","published-print":{"date-parts":[[1994,12]]}},"alternative-id":["10.1002\/jcp.1041610302"],"URL":"https:\/\/doi.org\/10.1002\/jcp.1041610302","archive":["Portico"],"relation":{},"ISSN":["0021-9541","1097-4652"],"issn-type":[{"value":"0021-9541","type":"print"},{"value":"1097-4652","type":"electronic"}],"subject":[],"published":{"date-parts":[[1994,12]]}}}