Amino-terminal Determinants of U-type Inactivation of Voltage-gated K+ Channels

The T1 domain is a cytosolic NH2-terminal domain present in all Kv (voltage-dependent potassium) channels, and is highly conserved between Kv channel subfamilies. Our characterization of a truncated form of Kv1.5 (Kv1.5ΔN209) expressed in myocardium demonstrated that deletion of the NH2 terminus of Kv1.5 imparts a U-shaped inactivation-voltage relationship to the channel, and prompted us to investigate the NH2 terminus as a regulatory site for slow inactivation of Kv channels. We examined the macroscopic inactivation properties of several NH2-terminal deletion mutants of Kv1.5 expressed in HEK 293 cells, demonstrating that deletion of residues up to the T1 boundary (Kv1.5ΔN19, Kv1.5ΔN91, and Kv1.5ΔN119) did not alter Kv1.5 inactivation, however, deletion mutants that disrupted the T1 structure consistently exhibited inactivation phenotypes resembling Kv1.5ΔN209. Chimeric constructs between Kv1.5 and the NH2 termini of Kv1.1 and Kv1.3 preserved the inactivation kinetics observed in full-length Kv1.5, again suggesting that the Kv1 T1 domain influences slow inactivation. Furthermore, disruption of intersubunit T1 contacts by mutation of residues Glu131 and Thr132to alanines resulted in channels exhibiting a U-shaped inactivation-voltage relationship. Fusion of the NH2terminus of Kv2.1 to the transmembrane segments of Kv1.5 imparted a U-shaped inactivation-voltage relationship to Kv1.5, whereas fusion of the NH2 terminus of Kv1.5 to the transmembrane core of Kv2.1 decelerated Kv2.1 inactivation and abolished the U-shaped voltage dependence of inactivation normally observed in Kv2.1. These data suggest that intersubunit T1 domain interactions influence U-type inactivation in Kv1 channels, and suggest a generalized influence of the T1 domain on U-type inactivation between Kv channel subfamilies. The T1 domain is a cytosolic NH2-terminal domain present in all Kv (voltage-dependent potassium) channels, and is highly conserved between Kv channel subfamilies. Our characterization of a truncated form of Kv1.5 (Kv1.5ΔN209) expressed in myocardium demonstrated that deletion of the NH2 terminus of Kv1.5 imparts a U-shaped inactivation-voltage relationship to the channel, and prompted us to investigate the NH2 terminus as a regulatory site for slow inactivation of Kv channels. We examined the macroscopic inactivation properties of several NH2-terminal deletion mutants of Kv1.5 expressed in HEK 293 cells, demonstrating that deletion of residues up to the T1 boundary (Kv1.5ΔN19, Kv1.5ΔN91, and Kv1.5ΔN119) did not alter Kv1.5 inactivation, however, deletion mutants that disrupted the T1 structure consistently exhibited inactivation phenotypes resembling Kv1.5ΔN209. Chimeric constructs between Kv1.5 and the NH2 termini of Kv1.1 and Kv1.3 preserved the inactivation kinetics observed in full-length Kv1.5, again suggesting that the Kv1 T1 domain influences slow inactivation. Furthermore, disruption of intersubunit T1 contacts by mutation of residues Glu131 and Thr132to alanines resulted in channels exhibiting a U-shaped inactivation-voltage relationship. Fusion of the NH2terminus of Kv2.1 to the transmembrane segments of Kv1.5 imparted a U-shaped inactivation-voltage relationship to Kv1.5, whereas fusion of the NH2 terminus of Kv1.5 to the transmembrane core of Kv2.1 decelerated Kv2.1 inactivation and abolished the U-shaped voltage dependence of inactivation normally observed in Kv2.1. These data suggest that intersubunit T1 domain interactions influence U-type inactivation in Kv1 channels, and suggest a generalized influence of the T1 domain on U-type inactivation between Kv channel subfamilies. voltage-gated potassium full-length Kv1.5 first transmembrane segment tetraethyl ammonium The inactivation mechanisms exhibited by different voltage-gated potassium (Kv)1 channels provide important physiological means by which the duration of action potentials in many excitable tissues is regulated at different frequencies and potentials. Inactivation of Kv channels has historically been divided into two categories, fast (N-type) inactivation which involves occlusion of the inner pore by an NH2-terminal ball, and slow (C-type) inactivation which involves a concerted constriction of the outer mouth of the channel pore (1Panyi G. Sheng Z. Tu L. Deutsch C. Biophys. J. 1995; 69: 896-903Abstract Full Text PDF PubMed Scopus (155) Google Scholar, 2Ogielska E.M. Aldrich R.W. J. Gen. Physiol. 1998; 112: 243-257Crossref PubMed Scopus (54) Google Scholar, 3Hoshi T. Zagotta W.N. Aldrich R.W. Neuron. 1991; 7: 547-556Abstract Full Text PDF PubMed Scopus (568) Google Scholar). However, recent studies have distinguished a second slow inactivation phenotype termed U-type inactivation, which has been characterized in several voltage-gated K+ channels, including Kv2.1 (4Klemic K.G. Shieh C.C. Kirsch G.E. Jones S.W. Biophys. J. 1998; 74: 1779-1789Abstract Full Text Full Text PDF PubMed Scopus (121) Google Scholar) and most recently in Shaker and Kv3.1 (5Klemic K.G. Kirsch G.E. Jones S.W. Biophys. J. 2001; 81: 814-826Abstract Full Text Full Text PDF PubMed Scopus (64) Google Scholar). U-type inactivation has been named for its characteristic U-shaped inactivation-voltage relationship, showing maximal inactivation at intermediate potentials where only a fraction of channels are open, and less pronounced inactivation at more positive potentials where channel opening has saturated (5Klemic K.G. Kirsch G.E. Jones S.W. Biophys. J. 2001; 81: 814-826Abstract Full Text Full Text PDF PubMed Scopus (64) Google Scholar). This U-shaped voltage- dependence of inactivation is caused by preferential inactivation from channel closed states, although the conformational changes underlying U-type inactivation remain unclear. Interestingly, whereas C-type inactivation is slowed by elevation of extracellular K+, this condition generally accelerates U-type inactivation, suggesting a distinct mechanism for channel inactivation (4Klemic K.G. Shieh C.C. Kirsch G.E. Jones S.W. Biophys. J. 1998; 74: 1779-1789Abstract Full Text Full Text PDF PubMed Scopus (121) Google Scholar, 5Klemic K.G. Kirsch G.E. Jones S.W. Biophys. J. 2001; 81: 814-826Abstract Full Text Full Text PDF PubMed Scopus (64) Google Scholar). In addition, our laboratory has recently demonstrated that a naturally occurring NH2-terminal truncated form of the cardiac potassium channel Kv1.5 (Kv1.5ΔN209) exhibits a U-type inactivation phenotype (6Attali B. Lesage F. Ziliani P. Guillemare E. Honoré E. Waldmann R. Hugnot J.-P. Mattéi M.-G. Lazdunski M. Barhanin J. J. Biol. Chem. 1993; 268: 24283-24289Abstract Full Text PDF PubMed Google Scholar, 7Fedida D. Wible B. Wang Z. Fermini B. Faust F. Nattel S. Brown A.M. Circ. Res. 1993; 73: 210-216Crossref PubMed Scopus (308) Google Scholar, 8Kurata H.T. Soon G.S. Fedida D. J. Gen. Physiol. 2001; 118: 315-332Crossref PubMed Scopus (31) Google Scholar). This finding clearly suggests that Kv1.5 possesses machinery to undergo both C-type and U-type inactivation, and directed our attention toward an investigation of the NH2 terminus as a potential regulatory site of U-type inactivation in Kv1.5 and other channels. A number of recent studies have investigated a modular architecture of potassium channel gating machinery, considering the membrane-bound segments of potassium channels as interchangeable pore modules and voltage-sensing modules (9Caprini M. Ferroni S. Planells-Cases R. Rueda J. Rapisarda C. Ferrer-Montiel A. Montal M. J. Biol. Chem. 2001; 276: 21070-21076Abstract Full Text Full Text PDF PubMed Scopus (25) Google Scholar, 10Lu Z. Klem A.M. Ramu Y. Nature. 2001; 413: 809-813Crossref PubMed Scopus (274) Google Scholar). However, structural and biochemical evidence for modularity Kv channels is to the NH2-terminal T1 a cytosolic that is highly conserved Kv channel subfamilies. for T1 of and channels that the T1 are as a which is to in the channel pore S. A. Full Text Full Text PDF PubMed Scopus Google Scholar). between different Kv channel the structural of the T1 domain is to all Kv channels A. S. Biol. PubMed Scopus Google Scholar, M. S. R. PubMed Scopus Google Scholar, A. S. Nature. 1998; PubMed Scopus Google Scholar). of the T1 is an in channel and and evidence suggest that the T1 as a distinct from the transmembrane channel a structure from the inner pore of Kv channels M. S. R. PubMed Scopus Google Scholar, M. S. R. Nature. 2001; PubMed Scopus Google Scholar, D. Deutsch C. 2001; PubMed Scopus Google Scholar, L. 2001; Full Text Full Text PDF PubMed Scopus Google Scholar, C. C. PubMed Scopus Google Scholar). The T1 domain influences channel including of channels Lazdunski M. S. A. PubMed Scopus Google Scholar, J. F. C. Nature. PubMed Scopus Google Scholar, S. J. Neuron. Full Text Full Text PDF PubMed Scopus Google Scholar, T. M. J. R. D. Y. PubMed Scopus Google many R. PubMed Scopus Google Scholar, J. D. D. E. J. PubMed Google Scholar, 1993; Full Text PDF PubMed Scopus Google and of between different Kv channel A. S. Nature. 1998; PubMed Scopus Google Scholar, C. C. PubMed Scopus Google Scholar, M. PubMed Scopus Google Scholar, Neuron. 1995; Full Text PDF PubMed Scopus Google Scholar, J. M. J. Biol. Chem. 1995; Full Text Full Text PDF PubMed Scopus Google Scholar). the interactions between the T1 and gating of channels have not been a number of recent studies have characterized the influence of the T1 domain on channel has been demonstrated that deletion and in the T1 domain alter the voltage dependence and kinetics of in channels, suggesting conformational of the T1 domain and the transmembrane segments of the channel D. S. Biol. 7: PubMed Scopus Google Scholar, C. Biol. PubMed Scopus Google Scholar, A. Full Text Full Text PDF PubMed Scopus Google Scholar). The influence of the T1 domain on channel inactivation has to investigate the for the of slow inactivation by the Kv1.5 NH2 have characterized the gating properties of a of NH2-terminal of Kv1.5, and constructs that the NH2 terminus of Kv1.5 the NH2 terminus of other Kv1 channels. Our that the NH2-terminal for of slow inactivation in Kv1.5 the T1 Furthermore, that fusion of the NH2 terminus of Kv2.1 to the transmembrane segments of Kv1.5 imparts a U-shaped inactivation-voltage relationship to Kv1.5, whereas the NH2terminus of Kv1.5 the U-type inactivation properties of Kv2.1. on HEK 293 in at in an In a of a in HEK 293 on in the of the channel the This the of an to the which expressed and on the of of channel and of in of to the HEK 293 in of to to and that to for HEK 293 full-length Kv1.5, Kv2.1 These HEK 293 Kv1.5, in and to The and to from from the and in a the at and the and data an and of and in all and are by the in the in D. at and at potentials have not been for potentials between and the the data are as of extracellular K+ and on Kv1.5 and inactivation. HEK to to in the of in the extracellular in the all from the and have been to the in data showing the of inactivation to as a fraction of in and extracellular are in the and HEK Kv1.5 to to in K+ and from the have been to the from NH2 termini of Kv1.5 and Kv2.1 influences on Kv channel inactivation. of The from Kv1.5 is as and the from Kv2.1 is and by the NH2 terminus up to in Kv1.5 NH2-terminal residues up to from and of the NH2 termini of Kv1.5 and Kv2.1 the T. Z. PubMed Scopus Google and a segment of the Kv2.1 NH2 terminus exhibiting the T1 domain of as in the to of and for and the Kv1.5 NH2 terminus inactivation in Kv2.1. data from and expressed in to inactivation-voltage as in the to inactivation of in and in The for of all channel constructs in this by constructs to for and to the The Kv1.5ΔN91, and mutants by from the of into a to a and The and mutants by of the residues to the terminus of The for and for are The channels in a and The by of of by of the of by of up to site in of the and channels, the Kv1.5 channel core at the site into in the of Kv1.1 and Kv1.3 and The fusion into for as by for of the of to the terminus of by that site at of and a site the The for the and for the are The to the of Kv1.5 to the terminus of Kv1.5, in a Kv1.5 of the NH2 terminus of by a site the and a site at of The as the and as the are The to the Kv1.5 of the Kv1.5 NH2 terminus up to by into a Kv1.5 of Kv1.5 the from of the the and its In channels, the T1 domain is to from the transmembrane segments of the channel, a in Interestingly, however, of the NH2 termini of Kv channels the gating properties of the A of this is the naturally occurring form of Kv1.5 a deletion of of the cytosolic NH2 terminus of Kv1.5, which exhibits and inactivation properties different from the of Kv1.5 H.T. Soon G.S. Fedida D. J. Gen. Physiol. 2001; 118: 315-332Crossref PubMed Scopus (31) Google Scholar). this examined the of Kv channels the in B. from a potential of to potentials between and in for by a to The of the observed at to the number of channels the in the to C. a potential of a to for at from between and in for by a to The the to for of The of the in is to the number of channels Kv1.5 channels expressed in HEK 293 exhibited a potential of and a potential of which studies from our laboratory and H.T. Soon G.S. Fedida D. J. Gen. Physiol. 2001; 118: 315-332Crossref PubMed Scopus (31) Google Scholar, D. S. J. Physiol. PubMed Scopus Google Scholar). In the in the of the inactivation-voltage relationship, Kv1.5 exhibiting a voltage dependence of inactivation at positive potentials The and inactivation properties of from observed in expressed in HEK 293 cells, exhibited a potential of which by to the Kv1.5 channel The potential in which by to Kv1.5 In addition, deletion of the Kv1.5 NH2 terminus to for inactivation, as more Kv1.5 the of potentials exhibited a U-shaped voltage dependence of inactivation, in which inactivation maximal at intermediate between and and less pronounced more positive This of the inactivation-voltage relationship the voltage dependence of inactivation observed in Kv1.5, and more the U-type inactivation properties of a channel as Kv2.1 Kv2.1 expressed in HEK 293 exhibited a potential of and a potential of and again clearly distinguished from C-type inactivation by a of its inactivation-voltage relationship. These clearly inactivation in Kv1.5 from the U-type inactivation phenotype of and and suggest that the NH2 terminus of Kv1.5 influence the inactivation properties of the The of the inactivation-voltage relationship in Kv1.5 a C-type inactivation generally as a inactivation that is to channel opening R. R. L. F. E. J. Gen. Physiol. PubMed Scopus Google Scholar). This studies of Kv1.5 and other Kv1 channels D. S. J. Physiol. PubMed Scopus Google Scholar, P. J. 1998; PubMed Scopus Google Scholar, J. Physiol. PubMed Google Scholar). Kv1.5 exhibits a number of other a C-type inactivation although to in Kv1.5 to extracellular inactivation in the of Kv1.5 by The of extracellular the observed Kv1.5 channels, extracellular in a of data demonstrating the of on the inactivation of are in A. the channel by to by only in the of extracellular a C-type mechanism of inactivation in Kv1.5, and to the inactivation mechanisms in Kv1.5 and examined the of elevation of extracellular K+ on inactivation in both channels. elevation of extracellular K+ in of Kv1.5 inactivation which suggests a C-type mechanism of inactivation in Kv1.5, and studies on Kv1.5 and other Shaker D. S. J. Physiol. PubMed Scopus Google Deutsch C. Biophys. J. Full Text PDF PubMed Scopus Google Scholar). In exhibits an to extracellular K+ more inactivation observed in extracellular This of inactivation to extracellular K+ to a of channels which a U-shaped inactivation-voltage relationship (5Klemic K.G. Kirsch G.E. Jones S.W. Biophys. J. 2001; 81: 814-826Abstract Full Text Full Text PDF PubMed Scopus (64) Google Scholar). and to the NH2-terminal in the inactivation phenotype of We by a of NH2-terminal truncated of Kv1.5 These expressed in HEK 293 cells, and and inactivation properties The and inactivation of Kv1.5 and have been for We examined constructs of the Kv1.5 NH2-terminal residues up to the T1 boundary (Kv1.5ΔN19, Kv1.5ΔN91, and of deletion constructs exhibited in inactivation gating from Kv1.5, although the in constructs to Kv1.5 and In addition, only observed in the of inactivation from Kv1.5ΔN91, and exhibited potentials of and and potentials of and all constructs exhibited a voltage dependence of inactivation at positive which the of the inactivation-voltage relationship characteristic of These data suggest that the first of Kv1.5 on the inactivation properties of the In a NH2-terminal deletion into the T1 domain resulted in of both and inactivation, and a U-shaped inactivation-voltage relationship resembling that for and These a U-type inactivation phenotype in both and and that into the T1 domain to the U-shaped inactivation-voltage relationship characteristic of Kv1.5ΔN209. exhibited and potentials of and the influence of the T1 several deletion mutants intermediate to and and Interestingly, of both and deletion intermediate deletion mutants to macroscopic the data that the first of the Kv1.5 T1 domain residues and a influence on U-type inactivation in We examined the and inactivation properties of a in which the first of the Kv1.5 T1 domain to in this of the T1 structure both channel and resulted in a U-shaped voltage dependence of inactivation and exhibited a potential of and a potential of These data that disruption of the first residues of the Kv1.5 T1 domain to the U-type inactivation phenotype observed in Kv1.5ΔN209. We examined the of residues in the recently of the T1 of Kv1.1 number A. S. Nature. 1998; PubMed Scopus Google Scholar) and number A. Full Text Full Text PDF PubMed Scopus Google and that this several that form intersubunit contacts between T1 This a recent that mutation of residues at the intersubunit T1 influence the gating properties of A. Full Text Full Text PDF PubMed Scopus Google Scholar). the of the T1 the NH2 terminus of Kv1.5 up to the NH2-terminal of Kv1.1 Kv1.3 in and examined and inactivation properties in HEK 293 that channels the Kv1 between T1 and in the of cytosolic NH2 termini T. Z. PubMed Scopus Google Scholar). of a inactivation-voltage relationship in constructs the T1 domain in the of U-type inactivation. The and exhibited potentials of and both the Kv1.1 and Kv1.3 NH2 termini to the inactivation properties observed in Kv1.5, as both channels exhibited a voltage dependence of inactivation at positive and inactivation to that observed in Kv1.5 The potentials of and and the data in and the of NH2-terminal the T1 domain of Kv1 channels, data provide evidence that the T1 domain are for U-type inactivation in Kv1 channels. of our deletion mutants of Kv1.5 recent that disruption of intersubunit T1 contacts influences the properties of A. Full Text Full Text PDF PubMed Scopus Google prompted us to the of on the inactivation properties of Kv1.5 A the between two T1 from the structure for the T1 domain of number The in A is in an channel, of the of the T1 in intersubunit contacts between residues the T1 although the first residues of and between the of A. S. Nature. 1998; PubMed Scopus Google Scholar, A. Full Text Full Text PDF PubMed Scopus Google Scholar). We a by two Glu131 and to alanines and of residues are in of the residues to Glu131 in in of gating A. Full Text Full Text PDF PubMed Scopus Google and our mutation in the disruption of a of intersubunit T1 contacts the NH2 terminus of the T1 domain in HEK 293 cells, exhibited a potential of and a potential of to Kv1.5 channels. These as of the residues to in have been to in a of the relationship A. Full Text Full Text PDF PubMed Scopus Google Scholar). channels consistently exhibited a inactivation-voltage relationship channels by at only by at not as pronounced as the U-shaped inactivation-voltage relationship more disruption of the T1 domain this clearly suggests that the T1 domain influence the inactivation phenotype in The data suggests that residues the T1 domain to U-type inactivation in investigate the of this between the NH2 terminus and the transmembrane core of voltage-gated Kv channels, a channel in which the NH2 terminus of Kv1.5 the NH2terminus of a voltage-gated K+ channel that exhibits of U-type inactivation The structural of the T1 domain is conserved all Kv channels, and that the Kv2.1 T1 domain exhibits the T1 domain of Kv1.5 A. S. Biol. PubMed Scopus Google Scholar, T. Z. PubMed Scopus Google Scholar). expressed this in HEK 293 and characterized its and inactivation exhibited and potentials of and and exhibited a U-shaped voltage dependence of inactivation The inactivation-voltage relationship of to observed in the of Kv1.5 and Kv2.1 and however, In did not as as Kv2.1 of Kv1.5 the examined We the in which the NH2terminus of Kv2.1 the NH2 terminus of Kv1.5 The and potentials of and fusion of the Kv1.5 NH2terminus to Kv2.1 resulted in of the normally observed in the Kv2.1 inactivation-voltage relationship and In addition, exhibited inactivation kinetics in full-length by to in Kv2.1 a Kv2.1 by at whereas by only at We examined an NH2-terminal form of Kv2.1 to that the of the Kv1.5 NH2 terminus in the not of deletion of the Kv2.1 NH2 We NH2-terminal of Kv2.1 in our HEK however, of in data from G. Brown A.M. Neuron. Full Text PDF PubMed Scopus Google Scholar). In of the T1 domain of Kv2.1 in of the kinetics of and of slow inactivation of the channel, in and a G. Brown A.M. Neuron. Full Text PDF PubMed Scopus Google Scholar). This from the which kinetics of and inactivation a a characterized a channel of the NH2 terminus of to the transmembrane of Kv2.1. This NH2-terminal in a U-shaped voltage dependence of inactivation in Kv1.5 in and inactivation kinetics in Kv2.1 that from the NH2-terminal deletion of Kv2.1 This suggests that the inactivation phenotype observed in the from a of the Kv1.5 NH2 The of voltage-gated structure suggests that the T1 from membrane-bound segments of the channel M. S. R. PubMed Scopus Google Scholar, M. S. R. Nature. 2001; PubMed Scopus Google Scholar, C. C. PubMed Scopus Google Scholar). has been demonstrated that deletion and highly on channel C. Biol. PubMed Scopus Google Scholar, A. Full Text Full Text PDF PubMed Scopus Google Scholar). These in of several studies demonstrating the of truncated of several Kv channels in including Kv1.5 and (6Attali B. Lesage F. Ziliani P. Guillemare E. Honoré E. Waldmann R. Hugnot J.-P. Mattéi M.-G. Lazdunski M. Barhanin J. J. Biol. Chem. 1993; 268: 24283-24289Abstract Full Text PDF PubMed Google Scholar, 7Fedida D. Wible B. Wang Z. Fermini B. Faust F. Nattel S. Brown A.M. Circ. Res. 1993; 73: 210-216Crossref PubMed Scopus (308) Google Scholar, M. J. J. Biol. Chem. Full Text Full Text PDF PubMed Scopus Google Scholar). NH2-terminal truncated channels an to by mechanisms as the T1 domain has been as a of and R. PubMed Scopus Google Scholar, J. D. D. E. J. PubMed Google Scholar, 1993; Full Text PDF PubMed Scopus Google Scholar, J. Physiol. PubMed Google Scholar). However, the influence of the T1 domain on channel and inactivation, has not been Our characterization of T1 of Kv1.5 recent studies in Shaker (5Klemic K.G. Kirsch G.E. Jones S.W. Biophys. J. 2001; 81: 814-826Abstract Full Text Full Text PDF PubMed Scopus (64) Google Scholar) suggest that Shaker K+ channels are to phenotypes characteristic of both C-type and U-type inactivation. In addition, the data in our suggests that the cytosolic NH2 terminus as Kv1.5, influences the of U-type inactivation, and the between and U-type Kv1.5 channels U-type inactivation D. S. J. Physiol. PubMed Scopus Google and up to the T1 on gating However, the T1 domain consistently disrupted both and inactivation properties of Kv1.5, in a to a U-type inactivation phenotype in the of the channel of channel deletion constructs of Kv1 channels and have demonstrated that this is the Kv1 T1 The of our studies in Kv1.5 suggest that the intersubunit T1 contacts in the U-type inactivation although the U-shaped inactivation-voltage relationship of the is not as as that observed in other T1 of Kv1.5 This the mutation only a fraction of the intersubunit T1 as intersubunit contacts between several residues the T1 domain that the T1 domain have been demonstrated to on the gating of Kv1 channels. This has been most examined residues at the intersubunit T1 residues the T1 and residues in the have been to channel gating D. S. Biol. 7: PubMed Scopus Google Scholar, A. Full Text Full Text PDF PubMed Scopus Google Scholar, A. A. L. Neuron. Full Text Full Text PDF PubMed Scopus Google J. Neuron. Full Text Full Text PDF PubMed Scopus (25) Google Scholar). In addition, T1 have been to both and of the relationship, on both the and properties of the In that disruption of the intersubunit T1 residues examined in our alter the slow inactivation properties of However, a more of the T1 the that more conformational changes in T1 are in the influence of this domain on channel A generalized for the NH2 terminus in of U-type inactivation by our studies of Kv1.5 and Kv2.1. These examined the of the NH2 termini of a C-type channel and a U-type channel of the Kv1.5 NH2 terminus the Kv2.1 NH2 terminus resulted in channels that exhibited a U-shaped inactivation-voltage relationship, to the inactivation phenotype observed in However, the resulted in a of inactivation Kv2.1 Our of that the Kv2.1 NH2terminus a channels in a that U-type inactivation. In the Kv1.5 T1 domain channels in a that U-type inactivation, which the of U-type inactivation in Kv1.5, and the of inactivation in Interestingly, the influence of the Kv1.5 NH2 terminus on the inactivation of Kv2.1 to the influence of as F. A. J. J. PubMed Google Scholar). In of Kv2.1 and in of both Kv2.1 and inactivation, and studies of constructs of Kv2.1 and have this to the NH2 terminus of the of T1 and the F. A. J. J. PubMed Google Scholar). are of Kv2.1 and although the regulatory in have not been Brown A.M. Kirsch G.E. J. Physiol. 1998; PubMed Google Scholar). In addition, as observed in our channel, channels of this NH2-terminal segment of and the transmembrane of Kv2.1 of Kv2.1 inactivation F. A. J. J. PubMed Google Scholar). These the of a generalized mechanism of between the NH2 termini and membrane-bound segments of voltage-gated K+ channels. in the of our the that the of the U-type inactivation phenotype by the NH2terminus a of voltage-gated to have several potential mechanisms for the conformational between T1 and the transmembrane of the The of the T1 domain is to the membrane-bound channel and T1 that gating have been to alter the of this of the channel, as M. S. R. PubMed Scopus Google Scholar). This suggests that the of the of the T1 domain on and this is the of in disruption of Kv2.1 inactivation Deutsch C. Biophys. J. Full Text PDF PubMed Scopus Google Scholar). However, other T1 in of T1 structure have been to suggesting an important for of T1 channel gating A. Full Text Full Text PDF PubMed Scopus Google Scholar). A mechanism for the influence of T1 is the terminus of Kv channels, as the NH2-terminal of T1 from the membrane-bound channel and the of the transmembrane segment are to form in channels PubMed Scopus Google Scholar). A. Full Text Full Text PDF PubMed Scopus Google Scholar) that the T1 domain of influence gating by the of channel closed Interestingly, of inactivation and suggest that the U-type voltage dependence of inactivation from inactivation from closed of the channel (4Klemic K.G. Shieh C.C. Kirsch G.E. Jones S.W. Biophys. J. 1998; 74: 1779-1789Abstract Full Text Full Text PDF PubMed Scopus (121) Google K.G. Kirsch G.E. Jones S.W. Biophys. J. 2001; 81: 814-826Abstract Full Text Full Text PDF PubMed Scopus (64) Google Scholar, 8Kurata H.T. Soon G.S. Fedida D. J. Gen. Physiol. 2001; 118: 315-332Crossref PubMed Scopus (31) Google Scholar). In our observed that all of the T1 and and which U-type inactivation to Kv1.5 in of channel is that the influence of the T1 domain on the of closed of the channel for both of and of inactivation from closed states, in a U-type inactivation is a of evidence suggesting that mechanisms underlying a U-type inactivation phenotype an important in channel This inactivation phenotype first in has been demonstrated in other voltage-gated K+ channels including Shaker and suggesting that U-type inactivation a more generalized of channels (4Klemic K.G. Shieh C.C. Kirsch G.E. Jones S.W. Biophys. J. 1998; 74: 1779-1789Abstract Full Text Full Text PDF PubMed Scopus (121) Google Scholar, 5Klemic K.G. Kirsch G.E. Jones S.W. Biophys. J. 2001; 81: 814-826Abstract Full Text Full Text PDF PubMed Scopus (64) Google Scholar). the conformational changes underlying U-type inactivation remain the cytosolic T1 domain of Kv channels to in the of U-type inactivation a site for a number of regulatory the T1 domain provide an important mechanism for of both and inactivation properties of Kv channels. We for the and Wang and for of

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