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• W2091470010 abstract "The activation of T-lymphocytes is dependent upon, and accompanied by, an increase in voltage-gated K+ conductance. Kv1.3, a Shaker family K+ channel protein, appears to play an essential role in the activation of peripheral human T cells. Although Kv1.3-mediated K+ currents increase markedly during the activation process in mice, and to a lesser degree in humans, Kv1.3 mRNA levels in these organisms do not, indicating post-transcriptional regulation. In other tissues Shaker K+ channel proteins physically associate with cytoplasmic β-subunits (Kvβ1–3). Recently it has been shown that Kvβ1 and Kvβ2 are expressed in mouse T cells and that they are up-regulated during mitogen-stimulated activation. In this study, we show that the human Kvβ subunits substantially increase K+ current amplitudes when coexpressed with their Kv1.3 counterpart, and that unlike in mouse, protein levels of human Kvβ2 remain constant upon activation. Differences in Kvβ2 expression between mice and humans may explain the differential K+ conductance increases which accompany T-cell proliferation in these organisms. The activation of T-lymphocytes is dependent upon, and accompanied by, an increase in voltage-gated K+ conductance. Kv1.3, a Shaker family K+ channel protein, appears to play an essential role in the activation of peripheral human T cells. Although Kv1.3-mediated K+ currents increase markedly during the activation process in mice, and to a lesser degree in humans, Kv1.3 mRNA levels in these organisms do not, indicating post-transcriptional regulation. In other tissues Shaker K+ channel proteins physically associate with cytoplasmic β-subunits (Kvβ1–3). Recently it has been shown that Kvβ1 and Kvβ2 are expressed in mouse T cells and that they are up-regulated during mitogen-stimulated activation. In this study, we show that the human Kvβ subunits substantially increase K+ current amplitudes when coexpressed with their Kv1.3 counterpart, and that unlike in mouse, protein levels of human Kvβ2 remain constant upon activation. Differences in Kvβ2 expression between mice and humans may explain the differential K+ conductance increases which accompany T-cell proliferation in these organisms. Voltage-gated K+ channels play an important role in the propagation of electrical signals in the nervous system of higher organisms (1Rudy B. Neuroscience. 1988; 25: 729-749Crossref PubMed Scopus (1070) Google Scholar). A large number of voltage-gated K+channel proteins are expressed throughout the mammalian nervous system. These proteins are encoded by a large number of genes which fall into various families or subfamilies of homology. The mammalianShaker family of K+ channels contains at least seven different genes, Kv1.1–Kv1.7 (2Coetzee W. Amarillo Y. Chiu J. Chow A. Lau D. McCormack T. Moreno H. Nadal M.S. Ozaita A. Pountney D. Saganich M. Vega-Saenz de Miera E. Rudy B. Ann. N. Y. Acad. Sci. 1999; 868: 233-285Crossref PubMed Scopus (977) Google Scholar), which form functional homo- and heterotetrameric channel complexes (3McCormack K. Lin J.W. Iverson L.E. Rudy B. Biochem. Biophys. Res. Commun. 1990; 171: 1361-1371Crossref PubMed Scopus (76) Google Scholar, 4Ruppersberg J.P. Schroter K.H. Sakmann B. Stocker M. Sewing S. Pongs O. Nature. 1990; 345: 535-537Crossref PubMed Scopus (340) Google Scholar). Furthermore, it has been shown that in the mammalian nervous system the channel-formingShaker proteins are usually complexed with cytoplasmic Kvβ subunits (Kvβ1–Kvβ3) (5Shamotienko O.G. Parcej D.N. Dolly J.O. Biochemistry. 1997; 36: 8195-8201Crossref PubMed Scopus (120) Google Scholar).Coexpression studies, utilizing mRNA injection and voltage-clamp analysis of Xenopus oocytes, have shown that the major brain Kvβ subunit (6Scott V.E.S. Rettig J. Parcej D.N. Keen J.N. Findlay J.B.C. Pongs O. Dolly J.O. Proc. Natl. Acad. Sci. 1994; 91: 1637-1641Crossref PubMed Scopus (176) Google Scholar), Kvβ2, and at least one splice form of Kvβ1 (Kvβ1a) are able to alter the inactivation properties of a number of neuronally expressed Kv1 channel proteins (7Rettig J. Heinemann S.H. Wunder F. Lorra C. Parcej D.N. Dolly J.O. Pongs O. Nature. 1994; 369: 289-294Crossref PubMed Scopus (740) Google Scholar, 8McCormack K. McCormack T. Tanouye M. Rudy B. Stuhmer W. FEBS Lett. 1995; 370: 32-36Crossref PubMed Scopus (94) Google Scholar). In contrast, neither of these two Kvβ subunits significantly alters the inactivation properties of Kv1.3, a K+ channel that is sparingly expressed within the nervous system (9Heinemann S. Rettig J. Scott V. Parcej D.N. Lorra C. Dolly J. Pongs O. J. Physiol. (Paris). 1994; 88: 173-180Crossref PubMed Scopus (35) Google Scholar). Perhaps more importantly, Kvβ subunits are also able to increase K+ current amplitudes of neuronal Kv1 K+ channels in the oocyte plasma membrane (8McCormack K. McCormack T. Tanouye M. Rudy B. Stuhmer W. FEBS Lett. 1995; 370: 32-36Crossref PubMed Scopus (94) Google Scholar). Furthermore, coexpression of several neuronal Kv1 channels with Kvβ2 in mammalian cell lines has shown that Kvβ2 increases the number of these Kv1 proteins reaching the membrane surface (10Shi G. Nakahira K. Hammond S. Rhodes K.J. Schechter L.E. Trimmer J.S. Neuron. 1996; 16: 843-852Abstract Full Text Full Text PDF PubMed Scopus (333) Google Scholar). Taken together, these studies indicate that the Kvβ subunits are likely to increase the surface expression offunctional, neuronal K+ channels.In addition to their role in the nervous system, K+ channel proteins are expressed in other cell types, where they may help determine membrane potential and maintain osmotic equilibrium. What specific physiological roles might these K+ channel proteins play outside the nervous system? They appear to play an essential role in the stimulation and maintenance of cellular proliferation of T cells (11Decoursey T.E. Chandy K.G. Gupta S. Cahalan M.D. J. Gen. Physiol. 1987; 89: 379-404Crossref PubMed Scopus (78) Google Scholar), B cells (12Sutro J.B. Vayuvegula B.S. Gupta S. Cahalan M.D. Adv. Exp. Med. Biol. 1989; 254: 113-122PubMed Google Scholar), macrophages (13Kitagawa S. Johnston Jr., R.B. J. Immunol. 1985; 135: 3417-3423PubMed Google Scholar), and brown adipocytes (14Pappone P.A. Am. J. Physiol. 1993; 264: C1014-C1019Crossref PubMed Google Scholar). In T-lymphocytes, the role has been extensively investigated: mitogens cause an immediate shift in K+conductance (15McKinnon D. Ceredig R. J. Exp. Med. 1986; 164: 1846-1861Crossref PubMed Scopus (37) Google Scholar, 16Cahalan M.D. Chandy K.G. DeCoursey T.E. Gupta S. J. Physiol. (Lond.). 1985; 358: 197-237Crossref Scopus (322) Google Scholar); activated T cells show substantially greater K+ conductances than quiescent cells (11Decoursey T.E. Chandy K.G. Gupta S. Cahalan M.D. J. Gen. Physiol. 1987; 89: 379-404Crossref PubMed Scopus (78) Google Scholar, 17Lee S.C. Sabath D.E. Deutsch C. Prystowsky M. J. Cell Biol. 1986; 102: 1200-1208Crossref PubMed Scopus (82) Google Scholar); activation is attenuated by membrane depolarization (18Gelfand E.W Cheung R.K. Mills G.B. Grinstein S. J. Immunol. 1987; 138: 527-531PubMed Google Scholar); and pharmacological agents that inhibit K+ channel conductances block T-cell proliferation (19DeCoursey T.E. Chandy K.G. Gupta S. Cahalan M.D. Nature. 1984; 307: 465-468Crossref PubMed Scopus (587) Google Scholar). In human peripheral T-lymphocytes, the Kv1.3 K+ channel plays a critical role in mediating the K+ current increase, which accompanies proliferation (20Decoursey T.E. Chandy K.G. Gupta S. Cahalan M.D. J. Gen. Physiol. 1987; 89: 405-420Crossref PubMed Scopus (86) Google Scholar), and is also likely to be the site of blockade, which inhibits this event (21Koo G.C. Blake J.T. Talento A. Nguyen M. Lin S. Sirotina A. Shah K. Mulvany K. Hora Jr., D. Cunningham P. Wunderler D.L. McManus O.B. Slaughter R. Bugianesi R. Felix J. Garcia M. Williamson J. Kaczorowski G. Sigal N.H. Springer M.S. Feeney W. J. Immunol. 1997; 158: 5120-5128PubMed Google Scholar). Interestingly, Kv1.3 mRNA does not appear to be up-regulated during proliferation, indicating that the Kv1.3 gene product is post-transcriptionally regulated (22Cai Y.C. Osborne P.B. North R.A. Dooley D.C. Douglass J. DNA Cell Biol. 1992; 11: 163-172Crossref PubMed Scopus (53) Google Scholar, 23Attali B. Romey G. Honore E. Schmid-Alliana A. Mattei M.G. Lesage F. Ricard P. Barhanin J. Lazdunski M. J. Biol. Chem. 1992; 267: 8650-8657Abstract Full Text PDF PubMed Google Scholar).Recent studies have shown that Kvβ2, and Kvβ1 to a lesser extent, are both expressed in mouse T-lymphocytes (24Autieri M.V. Belkowski S.M. Constantinescu C.S. Cohen J.A. Prystowsky M.B. J. Neuroimmunol. 1997; 77: 8-16Abstract Full Text Full Text PDF PubMed Scopus (17) Google Scholar). Moreover, the murine Kvβ mRNA and protein levels are markedly increased upon interleukin-2 stimulation. If the Kvβ subunits were able to increase the surface expression of Kv1.3 channels, then up-regulation of Kvβ subunits would result in greater K+ channel surface expression and therefore greater K+ conductance during the proliferation of T-lymphocytes and perhaps other cell types (11Decoursey T.E. Chandy K.G. Gupta S. Cahalan M.D. J. Gen. Physiol. 1987; 89: 379-404Crossref PubMed Scopus (78) Google Scholar, 12Sutro J.B. Vayuvegula B.S. Gupta S. Cahalan M.D. Adv. Exp. Med. Biol. 1989; 254: 113-122PubMed Google Scholar, 13Kitagawa S. Johnston Jr., R.B. J. Immunol. 1985; 135: 3417-3423PubMed Google Scholar, 14Pappone P.A. Am. J. Physiol. 1993; 264: C1014-C1019Crossref PubMed Google Scholar) The extent of Kvβ subunit up-regulation in response to T-cell activation could therefore account for the extent to which Kv1.3-mediated K+ current is elevated in different organisms. Utilizing the Xenopus oocyte expression system, we report the effects of coexpression of the human Kvβ1a and Kvβ2 subunits on the expressed current levels of Kv1.3 channels.DISCUSSIONT-lymphocytes are critical for eliciting cellular immune responses. It is well established that K+ channels play important roles in the activation of T-lymphocytes: important physiologic changes which T-lymphocytes undergo as a result of the activation process are inhibited by blockers of K+channels, including protein synthesis, cell volume increase, and cell-cycle progression (17Lee S.C. Sabath D.E. Deutsch C. Prystowsky M. J. Cell Biol. 1986; 102: 1200-1208Crossref PubMed Scopus (82) Google Scholar, 19DeCoursey T.E. Chandy K.G. Gupta S. Cahalan M.D. Nature. 1984; 307: 465-468Crossref PubMed Scopus (587) Google Scholar).It has been demonstrated that channels containing the Kv1.3 subunit are the major K+ channel (type n channel) in T-lymphocytes (25Lewis R.S. Cahalan M.D. Annu. Rev. Immunol. 1995; 13: 623-654Crossref PubMed Scopus (445) Google Scholar). The K+ conductance increases 20-fold in murine T-cells treated with mitogen, whereas in human T-cells, the K+ conductance increases roughly 2-fold (11Decoursey T.E. Chandy K.G. Gupta S. Cahalan M.D. J. Gen. Physiol. 1987; 89: 379-404Crossref PubMed Scopus (78) Google Scholar, 17Lee S.C. Sabath D.E. Deutsch C. Prystowsky M. J. Cell Biol. 1986; 102: 1200-1208Crossref PubMed Scopus (82) Google Scholar). However, treatment of these cells by a mitogen results in constant or decreased, rather than increased, Kv1.3 mRNA levels in mice and humans, respectively (22Cai Y.C. Osborne P.B. North R.A. Dooley D.C. Douglass J. DNA Cell Biol. 1992; 11: 163-172Crossref PubMed Scopus (53) Google Scholar, 23Attali B. Romey G. Honore E. Schmid-Alliana A. Mattei M.G. Lesage F. Ricard P. Barhanin J. Lazdunski M. J. Biol. Chem. 1992; 267: 8650-8657Abstract Full Text PDF PubMed Google Scholar). On the other hand, it has been shown that the expression of the murine Kvβ2 subunit increases markedly in response to stimulation by interleukin-2 (24Autieri M.V. Belkowski S.M. Constantinescu C.S. Cohen J.A. Prystowsky M.B. J. Neuroimmunol. 1997; 77: 8-16Abstract Full Text Full Text PDF PubMed Scopus (17) Google Scholar).Our results show that Kv1.3 can form functional channels alone but that the presence of Kvβ subunits, primarily Kvβ2, the more abundant β-subunit in human T-lymphocytes (24Autieri M.V. Belkowski S.M. Constantinescu C.S. Cohen J.A. Prystowsky M.B. J. Neuroimmunol. 1997; 77: 8-16Abstract Full Text Full Text PDF PubMed Scopus (17) Google Scholar), accelerates the functional assembly of Kv1.3 channels. The ability of the Kvβ2 subunit to enhance current levels of Kv1.3 may help to explain how the increase in Kvβ2 subunit expression can up-regulate the expression of Kv1.3 channels in activated murine lymphocytes. The much greater increase in Kvβ2 protein levels of mitogen-treated T-cells in mouse (24Autieri M.V. Belkowski S.M. Constantinescu C.S. Cohen J.A. Prystowsky M.B. J. Neuroimmunol. 1997; 77: 8-16Abstract Full Text Full Text PDF PubMed Scopus (17) Google Scholar), compared with human (Fig. 6), is consistent with the differential increase in K+ current observed in mitogen-treated T-cells in these two organisms. In fact, although K+ current levels in human mitogen-treated T-cells increase roughly 2-fold, this effect is immediate (19DeCoursey T.E. Chandy K.G. Gupta S. Cahalan M.D. Nature. 1984; 307: 465-468Crossref PubMed Scopus (587) Google Scholar), unlike in mouse (20Decoursey T.E. Chandy K.G. Gupta S. Cahalan M.D. J. Gen. Physiol. 1987; 89: 405-420Crossref PubMed Scopus (86) Google Scholar), ruling out transcriptional or translational regulation as the means by which the K+current level increases. The differences in β-subunit regulation in mice and humans may account for the vast difference in the extent to which Kv1.3 K+ conductance is up-regulated in activated T-cells in these two organisms. Voltage-gated K+ channels play an important role in the propagation of electrical signals in the nervous system of higher organisms (1Rudy B. Neuroscience. 1988; 25: 729-749Crossref PubMed Scopus (1070) Google Scholar). A large number of voltage-gated K+channel proteins are expressed throughout the mammalian nervous system. These proteins are encoded by a large number of genes which fall into various families or subfamilies of homology. The mammalianShaker family of K+ channels contains at least seven different genes, Kv1.1–Kv1.7 (2Coetzee W. Amarillo Y. Chiu J. Chow A. Lau D. McCormack T. Moreno H. Nadal M.S. Ozaita A. Pountney D. Saganich M. Vega-Saenz de Miera E. Rudy B. Ann. N. Y. Acad. Sci. 1999; 868: 233-285Crossref PubMed Scopus (977) Google Scholar), which form functional homo- and heterotetrameric channel complexes (3McCormack K. Lin J.W. Iverson L.E. Rudy B. Biochem. Biophys. Res. Commun. 1990; 171: 1361-1371Crossref PubMed Scopus (76) Google Scholar, 4Ruppersberg J.P. Schroter K.H. Sakmann B. Stocker M. Sewing S. Pongs O. Nature. 1990; 345: 535-537Crossref PubMed Scopus (340) Google Scholar). Furthermore, it has been shown that in the mammalian nervous system the channel-formingShaker proteins are usually complexed with cytoplasmic Kvβ subunits (Kvβ1–Kvβ3) (5Shamotienko O.G. Parcej D.N. Dolly J.O. Biochemistry. 1997; 36: 8195-8201Crossref PubMed Scopus (120) Google Scholar). Coexpression studies, utilizing mRNA injection and voltage-clamp analysis of Xenopus oocytes, have shown that the major brain Kvβ subunit (6Scott V.E.S. Rettig J. Parcej D.N. Keen J.N. Findlay J.B.C. Pongs O. Dolly J.O. Proc. Natl. Acad. Sci. 1994; 91: 1637-1641Crossref PubMed Scopus (176) Google Scholar), Kvβ2, and at least one splice form of Kvβ1 (Kvβ1a) are able to alter the inactivation properties of a number of neuronally expressed Kv1 channel proteins (7Rettig J. Heinemann S.H. Wunder F. Lorra C. Parcej D.N. Dolly J.O. Pongs O. Nature. 1994; 369: 289-294Crossref PubMed Scopus (740) Google Scholar, 8McCormack K. McCormack T. Tanouye M. Rudy B. Stuhmer W. FEBS Lett. 1995; 370: 32-36Crossref PubMed Scopus (94) Google Scholar). In contrast, neither of these two Kvβ subunits significantly alters the inactivation properties of Kv1.3, a K+ channel that is sparingly expressed within the nervous system (9Heinemann S. Rettig J. Scott V. Parcej D.N. Lorra C. Dolly J. Pongs O. J. Physiol. (Paris). 1994; 88: 173-180Crossref PubMed Scopus (35) Google Scholar). Perhaps more importantly, Kvβ subunits are also able to increase K+ current amplitudes of neuronal Kv1 K+ channels in the oocyte plasma membrane (8McCormack K. McCormack T. Tanouye M. Rudy B. Stuhmer W. FEBS Lett. 1995; 370: 32-36Crossref PubMed Scopus (94) Google Scholar). Furthermore, coexpression of several neuronal Kv1 channels with Kvβ2 in mammalian cell lines has shown that Kvβ2 increases the number of these Kv1 proteins reaching the membrane surface (10Shi G. Nakahira K. Hammond S. Rhodes K.J. Schechter L.E. Trimmer J.S. Neuron. 1996; 16: 843-852Abstract Full Text Full Text PDF PubMed Scopus (333) Google Scholar). Taken together, these studies indicate that the Kvβ subunits are likely to increase the surface expression offunctional, neuronal K+ channels. In addition to their role in the nervous system, K+ channel proteins are expressed in other cell types, where they may help determine membrane potential and maintain osmotic equilibrium. What specific physiological roles might these K+ channel proteins play outside the nervous system? They appear to play an essential role in the stimulation and maintenance of cellular proliferation of T cells (11Decoursey T.E. Chandy K.G. Gupta S. Cahalan M.D. J. Gen. Physiol. 1987; 89: 379-404Crossref PubMed Scopus (78) Google Scholar), B cells (12Sutro J.B. Vayuvegula B.S. Gupta S. Cahalan M.D. Adv. Exp. Med. Biol. 1989; 254: 113-122PubMed Google Scholar), macrophages (13Kitagawa S. Johnston Jr., R.B. J. Immunol. 1985; 135: 3417-3423PubMed Google Scholar), and brown adipocytes (14Pappone P.A. Am. J. Physiol. 1993; 264: C1014-C1019Crossref PubMed Google Scholar). In T-lymphocytes, the role has been extensively investigated: mitogens cause an immediate shift in K+conductance (15McKinnon D. Ceredig R. J. Exp. Med. 1986; 164: 1846-1861Crossref PubMed Scopus (37) Google Scholar, 16Cahalan M.D. Chandy K.G. DeCoursey T.E. Gupta S. J. Physiol. (Lond.). 1985; 358: 197-237Crossref Scopus (322) Google Scholar); activated T cells show substantially greater K+ conductances than quiescent cells (11Decoursey T.E. Chandy K.G. Gupta S. Cahalan M.D. J. Gen. Physiol. 1987; 89: 379-404Crossref PubMed Scopus (78) Google Scholar, 17Lee S.C. Sabath D.E. Deutsch C. Prystowsky M. J. Cell Biol. 1986; 102: 1200-1208Crossref PubMed Scopus (82) Google Scholar); activation is attenuated by membrane depolarization (18Gelfand E.W Cheung R.K. Mills G.B. Grinstein S. J. Immunol. 1987; 138: 527-531PubMed Google Scholar); and pharmacological agents that inhibit K+ channel conductances block T-cell proliferation (19DeCoursey T.E. Chandy K.G. Gupta S. Cahalan M.D. Nature. 1984; 307: 465-468Crossref PubMed Scopus (587) Google Scholar). In human peripheral T-lymphocytes, the Kv1.3 K+ channel plays a critical role in mediating the K+ current increase, which accompanies proliferation (20Decoursey T.E. Chandy K.G. Gupta S. Cahalan M.D. J. Gen. Physiol. 1987; 89: 405-420Crossref PubMed Scopus (86) Google Scholar), and is also likely to be the site of blockade, which inhibits this event (21Koo G.C. Blake J.T. Talento A. Nguyen M. Lin S. Sirotina A. Shah K. Mulvany K. Hora Jr., D. Cunningham P. Wunderler D.L. McManus O.B. Slaughter R. Bugianesi R. Felix J. Garcia M. Williamson J. Kaczorowski G. Sigal N.H. Springer M.S. Feeney W. J. Immunol. 1997; 158: 5120-5128PubMed Google Scholar). Interestingly, Kv1.3 mRNA does not appear to be up-regulated during proliferation, indicating that the Kv1.3 gene product is post-transcriptionally regulated (22Cai Y.C. Osborne P.B. North R.A. Dooley D.C. Douglass J. DNA Cell Biol. 1992; 11: 163-172Crossref PubMed Scopus (53) Google Scholar, 23Attali B. Romey G. Honore E. Schmid-Alliana A. Mattei M.G. Lesage F. Ricard P. Barhanin J. Lazdunski M. J. Biol. Chem. 1992; 267: 8650-8657Abstract Full Text PDF PubMed Google Scholar). Recent studies have shown that Kvβ2, and Kvβ1 to a lesser extent, are both expressed in mouse T-lymphocytes (24Autieri M.V. Belkowski S.M. Constantinescu C.S. Cohen J.A. Prystowsky M.B. J. Neuroimmunol. 1997; 77: 8-16Abstract Full Text Full Text PDF PubMed Scopus (17) Google Scholar). Moreover, the murine Kvβ mRNA and protein levels are markedly increased upon interleukin-2 stimulation. If the Kvβ subunits were able to increase the surface expression of Kv1.3 channels, then up-regulation of Kvβ subunits would result in greater K+ channel surface expression and therefore greater K+ conductance during the proliferation of T-lymphocytes and perhaps other cell types (11Decoursey T.E. Chandy K.G. Gupta S. Cahalan M.D. J. Gen. Physiol. 1987; 89: 379-404Crossref PubMed Scopus (78) Google Scholar, 12Sutro J.B. Vayuvegula B.S. Gupta S. Cahalan M.D. Adv. Exp. Med. Biol. 1989; 254: 113-122PubMed Google Scholar, 13Kitagawa S. Johnston Jr., R.B. J. Immunol. 1985; 135: 3417-3423PubMed Google Scholar, 14Pappone P.A. Am. J. Physiol. 1993; 264: C1014-C1019Crossref PubMed Google Scholar) The extent of Kvβ subunit up-regulation in response to T-cell activation could therefore account for the extent to which Kv1.3-mediated K+ current is elevated in different organisms. Utilizing the Xenopus oocyte expression system, we report the effects of coexpression of the human Kvβ1a and Kvβ2 subunits on the expressed current levels of Kv1.3 channels. DISCUSSIONT-lymphocytes are critical for eliciting cellular immune responses. It is well established that K+ channels play important roles in the activation of T-lymphocytes: important physiologic changes which T-lymphocytes undergo as a result of the activation process are inhibited by blockers of K+channels, including protein synthesis, cell volume increase, and cell-cycle progression (17Lee S.C. Sabath D.E. Deutsch C. Prystowsky M. J. Cell Biol. 1986; 102: 1200-1208Crossref PubMed Scopus (82) Google Scholar, 19DeCoursey T.E. Chandy K.G. Gupta S. Cahalan M.D. Nature. 1984; 307: 465-468Crossref PubMed Scopus (587) Google Scholar).It has been demonstrated that channels containing the Kv1.3 subunit are the major K+ channel (type n channel) in T-lymphocytes (25Lewis R.S. Cahalan M.D. Annu. Rev. Immunol. 1995; 13: 623-654Crossref PubMed Scopus (445) Google Scholar). The K+ conductance increases 20-fold in murine T-cells treated with mitogen, whereas in human T-cells, the K+ conductance increases roughly 2-fold (11Decoursey T.E. Chandy K.G. Gupta S. Cahalan M.D. J. Gen. Physiol. 1987; 89: 379-404Crossref PubMed Scopus (78) Google Scholar, 17Lee S.C. Sabath D.E. Deutsch C. Prystowsky M. J. Cell Biol. 1986; 102: 1200-1208Crossref PubMed Scopus (82) Google Scholar). However, treatment of these cells by a mitogen results in constant or decreased, rather than increased, Kv1.3 mRNA levels in mice and humans, respectively (22Cai Y.C. Osborne P.B. North R.A. Dooley D.C. Douglass J. DNA Cell Biol. 1992; 11: 163-172Crossref PubMed Scopus (53) Google Scholar, 23Attali B. Romey G. Honore E. Schmid-Alliana A. Mattei M.G. Lesage F. Ricard P. Barhanin J. Lazdunski M. J. Biol. Chem. 1992; 267: 8650-8657Abstract Full Text PDF PubMed Google Scholar). On the other hand, it has been shown that the expression of the murine Kvβ2 subunit increases markedly in response to stimulation by interleukin-2 (24Autieri M.V. Belkowski S.M. Constantinescu C.S. Cohen J.A. Prystowsky M.B. J. Neuroimmunol. 1997; 77: 8-16Abstract Full Text Full Text PDF PubMed Scopus (17) Google Scholar).Our results show that Kv1.3 can form functional channels alone but that the presence of Kvβ subunits, primarily Kvβ2, the more abundant β-subunit in human T-lymphocytes (24Autieri M.V. Belkowski S.M. Constantinescu C.S. Cohen J.A. Prystowsky M.B. J. Neuroimmunol. 1997; 77: 8-16Abstract Full Text Full Text PDF PubMed Scopus (17) Google Scholar), accelerates the functional assembly of Kv1.3 channels. The ability of the Kvβ2 subunit to enhance current levels of Kv1.3 may help to explain how the increase in Kvβ2 subunit expression can up-regulate the expression of Kv1.3 channels in activated murine lymphocytes. The much greater increase in Kvβ2 protein levels of mitogen-treated T-cells in mouse (24Autieri M.V. Belkowski S.M. Constantinescu C.S. Cohen J.A. Prystowsky M.B. J. Neuroimmunol. 1997; 77: 8-16Abstract Full Text Full Text PDF PubMed Scopus (17) Google Scholar), compared with human (Fig. 6), is consistent with the differential increase in K+ current observed in mitogen-treated T-cells in these two organisms. In fact, although K+ current levels in human mitogen-treated T-cells increase roughly 2-fold, this effect is immediate (19DeCoursey T.E. Chandy K.G. Gupta S. Cahalan M.D. Nature. 1984; 307: 465-468Crossref PubMed Scopus (587) Google Scholar), unlike in mouse (20Decoursey T.E. Chandy K.G. Gupta S. Cahalan M.D. J. Gen. Physiol. 1987; 89: 405-420Crossref PubMed Scopus (86) Google Scholar), ruling out transcriptional or translational regulation as the means by which the K+current level increases. The differences in β-subunit regulation in mice and humans may account for the vast difference in the extent to which Kv1.3 K+ conductance is up-regulated in activated T-cells in these two organisms. T-lymphocytes are critical for eliciting cellular immune responses. It is well established that K+ channels play important roles in the activation of T-lymphocytes: important physiologic changes which T-lymphocytes undergo as a result of the activation process are inhibited by blockers of K+channels, including protein synthesis, cell volume increase, and cell-cycle progression (17Lee S.C. Sabath D.E. Deutsch C. Prystowsky M. J. Cell Biol. 1986; 102: 1200-1208Crossref PubMed Scopus (82) Google Scholar, 19DeCoursey T.E. Chandy K.G. Gupta S. Cahalan M.D. Nature. 1984; 307: 465-468Crossref PubMed Scopus (587) Google Scholar). It has been demonstrated that channels containing the Kv1.3 subunit are the major K+ channel (type n channel) in T-lymphocytes (25Lewis R.S. Cahalan M.D. Annu. Rev. Immunol. 1995; 13: 623-654Crossref PubMed Scopus (445) Google Scholar). The K+ conductance increases 20-fold in murine T-cells treated with mitogen, whereas in human T-cells, the K+ conductance increases roughly 2-fold (11Decoursey T.E. Chandy K.G. Gupta S. Cahalan M.D. J. Gen. Physiol. 1987; 89: 379-404Crossref PubMed Scopus (78) Google Scholar, 17Lee S.C. Sabath D.E. Deutsch C. Prystowsky M. J. Cell Biol. 1986; 102: 1200-1208Crossref PubMed Scopus (82) Google Scholar). However, treatment of these cells by a mitogen results in constant or decreased, rather than increased, Kv1.3 mRNA levels in mice and humans, respectively (22Cai Y.C. Osborne P.B. North R.A. Dooley D.C. Douglass J. DNA Cell Biol. 1992; 11: 163-172Crossref PubMed Scopus (53) Google Scholar, 23Attali B. Romey G. Honore E. Schmid-Alliana A. Mattei M.G. Lesage F. Ricard P. Barhanin J. Lazdunski M. J. Biol. Chem. 1992; 267: 8650-8657Abstract Full Text PDF PubMed Google Scholar). On the other hand, it has been shown that the expression of the murine Kvβ2 subunit increases markedly in response to stimulation by interleukin-2 (24Autieri M.V. Belkowski S.M. Constantinescu C.S. Cohen J.A. Prystowsky M.B. J. Neuroimmunol. 1997; 77: 8-16Abstract Full Text Full Text PDF PubMed Scopus (17) Google Scholar). Our results show that Kv1.3 can form functional channels alone but that the presence of Kvβ subunits, primarily Kvβ2, the more abundant β-subunit in human T-lymphocytes (24Autieri M.V. Belkowski S.M. Constantinescu C.S. Cohen J.A. Prystowsky M.B. J. Neuroimmunol. 1997; 77: 8-16Abstract Full Text Full Text PDF PubMed Scopus (17) Google Scholar), accelerates the functional assembly of Kv1.3 channels. The ability of the Kvβ2 subunit to enhance current levels of Kv1.3 may help to explain how the increase in Kvβ2 subunit expression can up-regulate the expression of Kv1.3 channels in activated murine lymphocytes. The much greater increase in Kvβ2 protein levels of mitogen-treated T-cells in mouse (24Autieri M.V. Belkowski S.M. Constantinescu C.S. Cohen J.A. Prystowsky M.B. J. Neuroimmunol. 1997; 77: 8-16Abstract Full Text Full Text PDF PubMed Scopus (17) Google Scholar), compared with human (Fig. 6), is consistent with the differential increase in K+ current observed in mitogen-treated T-cells in these two organisms. In fact, although K+ current levels in human mitogen-treated T-cells increase roughly 2-fold, this effect is immediate (19DeCoursey T.E. Chandy K.G. Gupta S. Cahalan M.D. Nature. 1984; 307: 465-468Crossref PubMed Scopus (587) Google Scholar), unlike in mouse (20Decoursey T.E. Chandy K.G. Gupta S. Cahalan M.D. J. Gen. Physiol. 1987; 89: 405-420Crossref PubMed Scopus (86) Google Scholar), ruling out transcriptional or translational regulation as the means by which the K+current level increases. The differences in β-subunit regulation in mice and humans may account for the vast difference in the extent to which Kv1.3 K+ conductance is up-regulated in activated T-cells in these two organisms. We thank Herman Moreno for critical review of the manuscript." @default.
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• W2091470010 title "The Effects of Shaker β-Subunits on the Human Lymphocyte K+ Channel Kv1.3" @default.
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