Phosphorylation-dependent Regulation of Kv2.1 Channel Activity at Tyrosine 124 by Src and by Protein-tyrosine Phosphatase ε

Abstract

Voltage-gated potassium (Kv) channels are a complex and heterogeneous family of proteins that play major roles in brain and cardiac excitability. Although Kv channels are activated by changes in cell membrane potential, tyrosine phosphorylation of channel subunits can modulate the extent of channel activation by depolarization. We have previously shown that dephosphorylation of Kv2.1 by the nonreceptor-type tyrosine phosphatase PTPε (cyt-PTPε) down-regulates channel activity and counters its phosphorylation and up-regulation by Src or Fyn. In the present study, we identify tyrosine 124 within the T1 cytosolic domain of Kv2.1 as a target site for the activities of Src and cyt-PTPε. Tyr124 is phosphorylated by Src in vitro; in whole cells, Y124F Kv2.1 is significantly less phosphorylated by Src and loses most of its ability to bind the D245A substrate-trapping mutant of cyt-PTPε. Phosphorylation of Tyr124 is critical for Src-mediated up-regulation of Kv2.1 channel activity, since Y124F Kv2.1-mediated K+ currents are only marginally up-regulated by Src, in contrast with a 3-fold up-regulation of wild-type Kv2.1 channels by the kinase. Other properties of Kv2.1, such as expression levels, subcellular localization, and voltage dependence of channel activation, are unchanged in Y124F Kv2.1, indicating that the effects of the Y124F mutation are specific. Together, these results indicate that Tyr124 is a significant site at which the mutually antagonistic activities of Src and cyt-PTPε affect Kv2.1 phosphorylation and activity. Voltage-gated potassium (Kv) channels are a complex and heterogeneous family of proteins that play major roles in brain and cardiac excitability. Although Kv channels are activated by changes in cell membrane potential, tyrosine phosphorylation of channel subunits can modulate the extent of channel activation by depolarization. We have previously shown that dephosphorylation of Kv2.1 by the nonreceptor-type tyrosine phosphatase PTPε (cyt-PTPε) down-regulates channel activity and counters its phosphorylation and up-regulation by Src or Fyn. In the present study, we identify tyrosine 124 within the T1 cytosolic domain of Kv2.1 as a target site for the activities of Src and cyt-PTPε. Tyr124 is phosphorylated by Src in vitro; in whole cells, Y124F Kv2.1 is significantly less phosphorylated by Src and loses most of its ability to bind the D245A substrate-trapping mutant of cyt-PTPε. Phosphorylation of Tyr124 is critical for Src-mediated up-regulation of Kv2.1 channel activity, since Y124F Kv2.1-mediated K+ currents are only marginally up-regulated by Src, in contrast with a 3-fold up-regulation of wild-type Kv2.1 channels by the kinase. Other properties of Kv2.1, such as expression levels, subcellular localization, and voltage dependence of channel activation, are unchanged in Y124F Kv2.1, indicating that the effects of the Y124F mutation are specific. Together, these results indicate that Tyr124 is a significant site at which the mutually antagonistic activities of Src and cyt-PTPε affect Kv2.1 phosphorylation and activity. delayed rectifier, voltage-gated potassium channel nonreceptor form of PTPε glutathione S-transferase protein-tyrosine kinase protein-tyrosine phosphatase wild-type Voltage-dependent K+(Kv)1 channels are key regulators of cellular functions and affect parameters such as action potential wave forms, neuronal firing patterns, synaptic integration, neurotransmitter release, volume regulation, and cell proliferation (1Yi B.A. Minor Jr., D.L. Lin Y.F. Jan Y.N. Jan L.Y. Proc. Natl. Acad. Sci. U. S. A. 2001; 98: 11016-11023Crossref PubMed Scopus (71) Google Scholar). Proper function of Kv channels is vital to health and well being, as demonstrated by identification of mutations in genes that encode Kv channel subunits as causing cardiac and neurological disorders in humans (2Browne D.L. Gancher S.T. Nutt J.G. Brunt E.R. Smith E.A. Kramer P. Litt M. Nat. Genet. 1994; 8: 136-140Crossref PubMed Scopus (684) Google Scholar, 3Keating M.T. Sanguinetti M.C. Cell. 2001; 104: 569-580Abstract Full Text Full Text PDF PubMed Scopus (862) Google Scholar, 4Weinreich F. Jentsch T.J. Curr. Opin. Neurobiol. 2000; 10: 409-415Crossref PubMed Scopus (20) Google Scholar). Kv channels are composed of four α-subunits that span the cell membrane and that can be found in some cases in association with regulatory cytosolic औ-subunits (1Yi B.A. Minor Jr., D.L. Lin Y.F. Jan Y.N. Jan L.Y. Proc. Natl. Acad. Sci. U. S. A. 2001; 98: 11016-11023Crossref PubMed Scopus (71) Google Scholar, 5Pongs O. Semin. Neurosci. 1995; 7: 137-146Crossref Scopus (42) Google Scholar, 6Martens J.R. Kwak Y.G. Tamkun M.M. Trends Cardiovasc. Med. 1999; 9: 253-258Crossref PubMed Scopus (90) Google Scholar). All Kv channel α-subunits share a common core structure of six transmembrane segments (S1–S6) and a P-loop forming the pore region of the channel (7Yellen G. Nature. 2002; 419: 35-42Crossref PubMed Scopus (540) Google Scholar). α-Subunits contain several major structural domains. Among these is a voltage-sensing domain, composed of segments S1–S4 that folds in α-helical structure and surrounds the pore. This domain is responsible for energy transduction and for controlling gating behavior. A second major domain of α-subunits is the pore domain (segments S5-P-S6), whose structure is likely to be similar to the crystal structure of the bacterial KcsA K+ channel, with the inner helix S6 lining much of the pore (7Yellen G. Nature. 2002; 419: 35-42Crossref PubMed Scopus (540) Google Scholar). Another major domain of α-subunits is the T1 region, which is part of the cytosolic N-terminal domain. In Shaker-related Kv channels, this domain comprises ∼120 amino acids and is located between the N-terminal inactivation ball and S1 (8Cushman S.J. Nanao M.H. Jahng A.W. DeRubeis D. Choe S. Pfaffinger P.J. Nat. Struct. Biol. 2000; 7: 403-407Crossref PubMed Scopus (92) Google Scholar). The T1 domain is responsible for molecular segregation of Kv channels, in which tetramerization of α-subunits belonging to the same subfamily is preferred (8Cushman S.J. Nanao M.H. Jahng A.W. DeRubeis D. Choe S. Pfaffinger P.J. Nat. Struct. Biol. 2000; 7: 403-407Crossref PubMed Scopus (92) Google Scholar). In addition, this domain associates with the auxiliary औ-subunits ofShaker-related Kv channels and is the site for regulation of channel activity by various cytosolic factors (8Cushman S.J. Nanao M.H. Jahng A.W. DeRubeis D. Choe S. Pfaffinger P.J. Nat. Struct. 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EMBO J. 1998; 17: 4723-4734Crossref PubMed Scopus (75) Google Scholar). Interestingly, in rat retinal pigment epithelial cells, Src family tyrosine kinases can activate or inhibit Kv1.3 channel activity in a manner dependent on protein kinase C activity (26Strauss O. Rosenthal R. Dey D. Beninde J. Wollmann G. Thieme H Wiederbolt M. Invest. Ophtalmol. Vis. Sci. 2002; 43: 1645-1654PubMed Google Scholar). Last, an indirect role for the Kv1.5 α-subunits in phosphorylation of other subunits was recently shown. The Src homology 3 domains of Src family kinases can bind Kv1.5, thereby granting these PTKs access to Kv channel α-subunits that associate with Kv1.5 but that have no Src homology 3 binding sites of their own (27Nitabach M.N. Llamas D.A. Araneda R.C. Intile J.L. Thompson I.J. Zhou Y.I. Holmes T.C. Proc. Natl. Acad. Sci. U. S. A. 2001; 98: 705-710Crossref PubMed Scopus (47) Google Scholar). Protein-tyrosine phosphatases (PTPs) are generic antagonists of PTKs and play crucial roles in regulating physiological processes by affecting protein phosphorylation (28Hunter T. Cell. 1995; 80: 225-236Abstract Full Text PDF PubMed Scopus (2608) Google Scholar, 29Tonks N.K. Neel B.G. Curr. Opin. Cell Biol. 2001; 13: 182-195Crossref PubMed Scopus (464) Google Scholar, 30Andersen J.N. Mortensen O.H. Peters G.H. Drake P.G. Iversen L.F. Olsen O.H. Jansen P.G. Andersen H.S. Tonks N.K. Moller N.P. Mol. Cell. Biol. 2001; 21: 7117-7136Crossref PubMed Scopus (603) Google Scholar). However, in contrast with the wealth of information concerning the effects of PTKs on Kv channels, very little is known about how PTPs participate in these processes. The receptor-type PTPα (31Sap J. D'Eustachio P. Givol D. Schlessinger J. Proc. Natl. Acad. Sci. U. S. A. 1990; 87: 6112-6116Crossref PubMed Scopus (140) Google Scholar, 32Krueger N.X. Streuli M. Saito H. 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Sobko A. Shinder V. Attali B. Elson A. EMBO J. 2000; 19: 4036-4045Crossref PubMed Scopus (84) Google Scholar). In agreement with these results, both Kv1.5 and Kv2.1 were hyperphosphorylated in primary Schwann cells and in sciatic nerve tissue from mice genetically lacking PTPε. These effects were correlated with increased Kv channel currents in PTPε-deficient Schwann cells, as well as with transient but severe hypomyelination of sciatic nerve axons in PTPε-deficient mice (36Peretz A. Gil-Henn H. Sobko A. Shinder V. Attali B. Elson A. EMBO J. 2000; 19: 4036-4045Crossref PubMed Scopus (84) Google Scholar). for Kv2.1 a of cyt-PTPε was in which established that a substrate-trapping mutant of cyt-PTPε and with Kv2.1 (36Peretz A. Gil-Henn H. Sobko A. Shinder V. Attali B. Elson A. EMBO J. 2000; 19: 4036-4045Crossref PubMed Scopus (84) Google Scholar, T. D. Tonks N.K. Proc. Natl. Acad. Sci. U. S. A. 1997; 94: PubMed Scopus Google Scholar). between this mutant and Kv2.1 were by indicating that were by the site of cyt-PTPε binding to at in The of that In the present study, we identify a tyrosine located in the T1 cytosolic domain of Kv2.1, as an site for phosphorylation by We also identify the same as a site for the substrate-trapping mutant of that is by this Phosphorylation of Tyr124 has significant effects on Src-mediated regulation of Kv2.1 channel activity, since this to a most of the ability of Src to channel activity affecting other properties of the These results Tyr124 as an site for mutually antagonistic regulation of Kv2.1 by Src and by cyt-PTPε and the role of in the T1 domain in affecting Kv2.1 activity. The following were in this study, in the expression mouse cyt-PTPε (35Elson A. Leder P. Proc. Natl. Acad. Sci. U. S. A. 1995; 92: 12235-12239Crossref PubMed Scopus (75) Google D245A cyt-PTPε (36Peretz A. Gil-Henn H. Sobko A. Shinder V. Attali B. Elson A. EMBO J. 2000; 19: 4036-4045Crossref PubMed Scopus (84) Google rat Kv2.1 of J. and M. and wild-type and Src of S. PTPε a at their C The Y124F mutation was the rat Kv2.1 by the of the mutation and of other mutations were by in this A. Leder P. J. Biol. Chem. 1995; Full Text Full Text PDF PubMed Scopus Google and HEK 293 cells were in with and were transfected the C. H. Mol. Cell. Biol. 7: PubMed Scopus Google Scholar). 293 cells were on previously with transfected with the expression and with as previously H. G. H. S. Elson A. 2000; 19: PubMed Scopus Google Scholar). were or or cells were with the of a system and an on a were in A with and and were as H. G. H. S. Elson A. 2000; 19: PubMed Scopus Google Scholar). protein following was by of molecular proteins of the the of in was by the with In of protein were to and the of were in a to the of on the substrate-trapping cells were in A with and of cellular proteins was with for by with A and with was by the and The which a Tyr124 of Kv2.1 and which was the sites of The in which Tyr124 was by an was in a similar manner Y124F and Y124F The structure of the was by proteins were in and by binding to and with Src was in 293 cells and was phosphorylation were in of kinase to which of Src, to of and of proteins were were at for were on and present in proteins was with a of the of proteins present in the was by of and by with of of Src were with Xenopus were from Xenopus The for and of were by the of were with of the were and with in and to with for to and oocytes were for and were at in with and Kv2.1 or Y124F Kv2.1 similar of for Src were also voltage were as previously I. Peretz A. C. Busch A.E. Attali B. EMBO J. 1999; 18: PubMed Scopus Google Scholar) following were in a and to with a at a of was to to the of cell currents were at a were with 3 and of of the and and were the and a with a were at and at the potential was was the of the was the and All were as significant between were by studies have shown that tyrosine phosphorylation of Kv2.1 by Src and Fyn up-regulates channel activity, dephosphorylation of Kv2.1 by cyt-PTPε counters this (36Peretz A. Gil-Henn H. Sobko A. Shinder V. Attali B. Elson A. EMBO J. 2000; 19: 4036-4045Crossref PubMed Scopus (84) Google Scholar). This that both on the and on the other affect phosphorylation of the same of tyrosine in The Kv2.1 has tyrosine of which are located in or in segments and are to cytosolic or the six are located in the N-terminal cytosolic domain, are within the domain, and is located in the cytosolic between the and domains. of the tyrosine in Kv2.1 that only of these, Tyr124 of the N-terminal cytosolic T1 domain, is in a that is similar to the for Src phosphorylation of Trends Sci. 1995; 20: Full Text PDF PubMed Scopus Google Scholar). In to Src phosphorylate Tyr124 of Kv2.1 in we the ability of Src to phosphorylate a from the of Kv2.1, which was Tyr124 and in which this was the only A similar in which Tyr124 was with a as a were as glutathione S-transferase proteins in and were by and by as of both proteins were with Src and with and phosphorylation was to for phosphorylation of the protein was in these studies the of the protein tyrosine this that some of the tyrosine of were in agreement with results H. Elson A. 1999; 18: PubMed Scopus Google Scholar). In similar phosphorylation were in protein to which no been In phosphorylation of the in which Tyr124 was was that of This that Tyr124 can be phosphorylated by Src in and is with results by phosphorylation at this In to the potential role of Tyr124 in regulation of Kv2.1 in the of the Kv2.1 we this to expression in cells, and Y124F Kv2.1 to the cell membrane in similar as by of cells protein Although cyt-PTPε is of cyt-PTPε are to the cell and some cyt-PTPε is found within the cell (35Elson A. Leder P. Proc. Natl. Acad. Sci. U. S. A. 1995; 92: 12235-12239Crossref PubMed Scopus (75) Google Scholar, H. G. H. S. Elson A. 2000; 19: PubMed Scopus Google J. G. H. Elson A. Cell Res. 2002; 281: PubMed Scopus Google Scholar). in both and Y124F Kv2.1 with indicating that both similar to with the In addition, both and Y124F Kv2.1 channels were at similar following cells We that the Y124F mutation significantly affect the subcellular or expression of phosphorylation of Y124F Kv2.1 by HEK 293 cells were transfected with activated Src, with or mutant were and with which were on is Kv2.1 the and expression of Kv2.1 and of Src in cell are from an of of Kv2.1 to cellular Kv2.1 protein and indicate that Y124F Kv2.1 phosphorylation is of that of Kv2.1 by of Kv2.1 with Src in phosphorylation of the channel, in agreement with studies (36Peretz A. Gil-Henn H. Sobko A. Shinder V. Attali B. Elson A. EMBO J. 2000; 19: 4036-4045Crossref PubMed Scopus (84) Google Scholar). In Src-mediated phosphorylation of Y124F Kv2.1 was by similar Interestingly, of cyt-PTPε in the same system phosphorylation of both and Y124F Kv2.1 by Src These results that cyt-PTPε can counter Src-mediated phosphorylation of Kv2.1 at Tyr124 and most likely at other sites as We have recently shown that PTPε can and activate Src H. Elson A. J. Biol. Chem. Google Scholar). The of cyt-PTPε on Kv2.1 in the studies was to cyt-PTPε affecting Src activity, since this Src, which the tyrosine that can be by PTPε. dephosphorylation of Src by cyt-PTPε Src H. Elson A. J. Biol. Chem. Google Scholar) and have to phosphorylation of These results, with the in Src-mediated phosphorylation of Tyr124 shown indicate that Tyr124 is a significant site of phosphorylation by Src in In a of binding of the substrate-trapping mutant D245A cyt-PTPε to Y124F Kv2.1 was of this are but in cases can and bind their phosphorylated substrates to of the mutant with its T. D. Tonks N.K. Proc. Natl. Acad. Sci. U. S. A. 1997; 94: PubMed Scopus Google Scholar). D245A cyt-PTPε and Kv2.1 from transfected cells However, less Y124F Kv2.1 was with D245A cyt-PTPε expression of similar of and Y124F Kv2.1 channels in these cells of Kv channel with D245A cyt-PTPε was significantly these were in the of the critical of the of PTPs G. S. J. J. P. B. G. M.J. C. J. Biol. Chem. 1997; Full Text Full Text PDF PubMed Scopus Google thereby the binding of PTP to their substrates T. D. Tonks N.K. Proc. Natl. Acad. Sci. U. S. A. 1997; 94: PubMed Scopus Google Scholar). This that the binding was to association of the site of cyt-PTPε with phosphorylated of D245A cyt-PTPε were of Src, thereby in the results to phosphorylation of by the kinase. In these results indicate that Tyr124 is a significant site to which the of cyt-PTPε by the of the Y124F mutation on Kv2.1 channel activity, we and Y124F Kv2.1 channels in Xenopus oocytes in the or of that expression of Kv2.1 channels delayed K+ currents that activated Src up-regulated Kv2.1 by with no significant changes in activation and voltage dependence of Y124F Kv2.1 channels K+ currents that were very similar to by Kv2.1 with no significant in or in and voltage dependence of activation In contrast to Kv2.1 channels, Src increased Y124F Kv2.1 by only The Y124F Kv2.1 channels are and are activated by in the of Src in a manner similar to the Tyr124 Kv2.1 channels. However, mutant Y124F Kv2.1 channels are and in their ability to up-regulation by Src-mediated the role of Tyr124 in regulating this the of Tyr124 of Kv2.1 as a site that is phosphorylated by and in Phosphorylation at Tyr124 for of Src phosphorylation of Kv2.1, for a similar of binding to D245A and for of the ability of Src to Kv2.1 activation by membrane depolarization. of the effects of Src are by the role of this is very Kv channels are activated by membrane with phosphorylation as a of this is that mutant Y124F and the wild-type Tyr124 Kv2.1 channels were activated by to the same extent in the of Src and that the of Src phosphorylation was to their affecting other In this with the of the Y124F mutation and the expression and subcellular of Y124F Kv2.1 channels, the but of the Kv2.1 by the Y124F The same results Tyr124 as a significant target site for the mutually effects of Src and cyt-PTPε on of tyrosine as sites for PTP activity of the PTP in but also of PTKs that phosphorylate these on the part of a a tyrosine the of to the PTP and the this binding studies of D245A cyt-PTPε were of Src, on phosphorylation of Kv2.1 by PTKs present in HEK 293 These cells of Src as well as other tyrosine The that these the Y124F mutation was found to affect cyt-PTPε binding the of this site also in the of Src activity. its significant on results indicate that Src phosphorylation affect and of activation of or Y124F is that Src family tyrosine kinases the of channels that tyrosine phosphorylation the channel as previously R. Science. 1997; PubMed Scopus Google Scholar). The this is known at but is likely by changes in the cytosolic T1 domain by phosphorylation of Tyr124 and that affect properties of the of Tyr124 is in the only other known family as well as in This is in most other of Kv channel known family contain an at the proteins contain proteins contain or cyt-PTPε has been shown to counter activation of Kv1.5 by Src and by Fyn in HEK 293 cells and in Xenopus oocytes the of a tyrosine at the (36Peretz A. Gil-Henn H. Sobko A. Shinder V. Attali B. Elson A. EMBO J. 2000; 19: 4036-4045Crossref PubMed Scopus (84) Google Scholar). This that a similar of mutually antagonistic regulation by cyt-PTPε and a Src family tyrosine in other Kv channels. of Kv2.1 channels by PTKs and PTPs be for the of cell in of In both and of the and Kv2.1 channels are on and but on axons J. P. 1998; PubMed Scopus Google Scholar). studies that channels play a role in regulating of synaptic J. E. J. Physiol. 2000; PubMed Scopus Google Scholar). In this the of Kv2.1 by PTKs and PTPs play a role in synaptic synaptic channels, which are found to the firing of neurons S.A. J.M. J. Neurosci. 2002; PubMed Google Scholar) and the of neurons G. T. J. Neurosci. 1999; 19: PubMed Google be to such by PTKs and In the of Kv2.1 channel activity the tyrosine phosphorylation of its Tyr124 play a crucial role in regulating neuronal in various of the We J. and M. for of