Fast Inactivation of Voltage-dependent Calcium Channels

We recently described domains II and III as important determinants of fast, voltage-dependent inactivation of R-type calcium channels (Spaetgens, R. L., and Zamponi, G. W. (1999) J. Biol. Chem. 274, 22428–22438). Here we examine in greater detail the structural determinants of inactivation using a series of chimeras comprising various regions of wild type α1C and α1Ecalcium channels. Substitution of the II S6 and/or III S6 segments of α1E into the α1C backbone resulted in rapid inactivation rates that closely approximated those of wild type α1E channels. However, neither individual or combined substitution of the II S6 and III S6 segments could account for the 60 mV more negative half-inactivation potential seen with wild type α1E channels, indicating that the S6 regions contribute only partially to the voltage dependence of inactivation. Interestingly, the converse replacement of α1E S6 segments of domains II, III, or II+III with those of α1Cwas insufficient to significantly slow inactivation rates. Only when the I-II linker region and the domain II and III S6 regions of α1E were concomitantly replaced with α1Csequence could inactivation be abolished. Conversely, introduction of the α1E domain I-II linker sequence into α1C conferred α1E-like inactivation rates, indicating that the domain I-II linker is a key contributor to calcium channel inactivation. Overall, our data are consistent with a mechanism in which inactivation of voltage-dependent calcium channels may occur via docking of the I-II linker region to a site comprising, at least in part, the domain II and III S6 segments. We recently described domains II and III as important determinants of fast, voltage-dependent inactivation of R-type calcium channels (Spaetgens, R. L., and Zamponi, G. W. (1999) J. Biol. Chem. 274, 22428–22438). Here we examine in greater detail the structural determinants of inactivation using a series of chimeras comprising various regions of wild type α1C and α1Ecalcium channels. Substitution of the II S6 and/or III S6 segments of α1E into the α1C backbone resulted in rapid inactivation rates that closely approximated those of wild type α1E channels. However, neither individual or combined substitution of the II S6 and III S6 segments could account for the 60 mV more negative half-inactivation potential seen with wild type α1E channels, indicating that the S6 regions contribute only partially to the voltage dependence of inactivation. Interestingly, the converse replacement of α1E S6 segments of domains II, III, or II+III with those of α1Cwas insufficient to significantly slow inactivation rates. Only when the I-II linker region and the domain II and III S6 regions of α1E were concomitantly replaced with α1Csequence could inactivation be abolished. Conversely, introduction of the α1E domain I-II linker sequence into α1C conferred α1E-like inactivation rates, indicating that the domain I-II linker is a key contributor to calcium channel inactivation. Overall, our data are consistent with a mechanism in which inactivation of voltage-dependent calcium channels may occur via docking of the I-II linker region to a site comprising, at least in part, the domain II and III S6 segments. kilobase(s) base pair(s) cesium methanesulfonate tetraethylammonium Calcium entry through voltage-dependent calcium channels is important for a range of cellular processes, including neurotransmitter release and activation of Ca2+-dependent enzymes. Molecular cloning has identified the primary structures of at least 9 different neuronal Ca2+ channel α1 subunits (termed α1A through α1I (1Williams M.E. Feldman D.H. McCue A.F. Brenner R. Velicelebi G. Ellis S.B. Harpold M.M. 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Calcium channels, like many other voltage-dependent ion channels, undergo a series of conformational changes in response to voltage, resulting in their opening, closing, and inactivation. Voltage-dependent inactivation of calcium channels is an important intrinsic process that prevents the breakdown of the calcium gradient as well as excessive calcium entry that is toxic to most cells (18Choi D.W. Trends Neurosci. 1988; 11: 465-469Abstract Full Text PDF PubMed Scopus (1609) Google Scholar, 19Orrenius S. McConkey D.J. Bellomo G. Nicotera P. Trends Pharmacol. Sci. 1989; 10: 281-285Abstract Full Text PDF PubMed Scopus (790) Google Scholar, 20Orrenius S. Nicotera P. J. Neural Transm. Suppl. 1994; 43: 1-11PubMed Google Scholar). In addition, many pharmacological agents interact predominantly with inactivated channels (21Hawthorn M.H. Ferrante J.N. Kwon Y.W. Rutledge A. Luchowski E. Bangalore R. Triggle D.J. Eur. J. Pharmacol. 1992; 229: 143-148Crossref PubMed Scopus (15) Google Scholar, 22Hering S. Aczel S. Kraus R.L. Berjukow S. Striessnig J. Timin E.N. Proc. Natl. Acad. Sci. U. S. A. 1997; 94: 13323-13328Crossref PubMed Scopus (62) Google Scholar). Unlike sodium (23Vassilev P. Scheuer T. Catterall W.A. Proc. Natl. Acad. Sci. U. S. A. 1989; 86: 8147Crossref PubMed Scopus (172) Google Scholar, 24Eaholtz G. Scheuer T. Catterall W.A. Neuron. 1994; 12: 1041-1048Abstract Full Text PDF PubMed Scopus (136) Google Scholar) and potassium (25Zagotta W.N. Hoshi T. Aldrich R.W. Science. 1990; 250: 506-507Crossref PubMed Scopus (609) Google Scholar, 26Hoshi T. Zagotta W.N. Aldrich R.W. Neuron. 1991; 7: 436-454Abstract Full Text PDF Scopus (569) Google Scholar, 27Isacoff E.Y. Jan Y.N. Jan L.Y. Nature. 1991; 342: 86-90Crossref Scopus (276) Google Scholar) channels, the mechanisms that govern calcium channel voltage-dependent inactivation are not fully understood. Although a number of structural moieties of the calcium channel α1 subunit have been implicated in being important in fast calcium channel inactivation (7Bourinet E. Soong T.W. Sutton K. Slaymaker S. Mathews E. Monteil A. Zamponi G.W. Nargeot J. Snutch T.P. Nat. Neurosci. 1999; 2: 407-415Crossref PubMed Scopus (364) Google Scholar,22Hering S. Aczel S. Kraus R.L. Berjukow S. Striessnig J. Timin E.N. Proc. Natl. Acad. Sci. U. S. A. 1997; 94: 13323-13328Crossref PubMed Scopus (62) Google Scholar, 28Zhang J.F. Ellinor P.T. Aldrich R.W. Tsien R.W. Nature. 1994; 372: 97-100Crossref PubMed Scopus (177) Google Scholar, 29Zamponi G.W. Soong T.W. Bourinet E. Snutch T.P. J. Neurosci. 1996; 16: 2430-2443Crossref PubMed Google Scholar, 30Herlitze S. Hockerman G.H. Scheuer T. Catterall W.A. Proc. Natl. Acad. Sci. U. S. A. 1997; 94: 1402-1406Crossref PubMed Scopus (169) Google Scholar, 32Hering S. Aczel S. Grabner M. Doring F. Berjukow S. Mitterdorfer J. Sinnegger M.J. Striessnig J. Degtiar V.E. Wang Z. Glossmann H. J. Biol. Chem. 1996; 271: 24471-24475Abstract Full Text Full Text PDF PubMed Scopus (75) Google Scholar, 33Hering S. Berjukow S. Aczel S. Timin E.N. Trends Pharmacol. Sci. 1998; 19: 439-443Abstract Full Text Full Text PDF PubMed Scopus (62) Google Scholar), the detailed mechanism underlying the inactivation process remain unknown, and there have been few systematic attempts to resolve this issue. By creating a series of chimeras between non-inactivating (L-type) α1C and rapidly inactivating (R-type) α1E rat brain calcium channels, we recently demonstrated that multiple structural domains determine the voltage dependence and rates of calcium channel inactivation (34Spaetgens R.L. Zamponi G.W. J. Biol. Chem. 1999; 274: Full Text Full Text PDF PubMed Scopus Google Scholar). we the domain II and III S6 segments and the domain I-II linker region as key in the of calcium channel inactivation. a number of chimeras α1C and α1E channels, we that of the domain II III or I-II linker regions of α1E into α1C is to α1E-like inactivation with of inactivation α1E the substitution of regions with α1C this we a in which the I-II linker a that may at the domain II and III S6 regions of the We previously and into the for rat brain α1E number and α1C number at the of the I-II and at the of the linker R.L. Zamponi G.W. J. Biol. Chem. 1999; 274: Full Text Full Text PDF PubMed Scopus Google Scholar) to the of a series of chimeras various of domains of the channels. of the domain II and III S6 an of into of chimeras at an site to the of the II S6 and an site to the of the III S6 to the of II S6 and III S6 are in channels, and the chimeras only in their S6 of the domain I-II linker a site into the sequence at the of domain and chimeras the were as the for to the of the II S6 segments. were with and to their with the we at of and of of the and the region to the of the and were with and and the resulting were via the into to α1E and and chimeras the were as the for to the of the III S6 segments. the a at of and a at of were However, the of a substitution to the in the sequence to the substitution in the of the and the region to the of the and were with and and the resulting were and to α1E and α1E and α1E were the into α1E to α1E to α1C α1C α1C In the using a site at the of the domain I-II linker regions of and at in a of that is between channels and into to the of to the the sequence I-II linker and into and were with and the the to domains III and of into the of the via we a site into the sequence the of the domain I-II linker an site at an the of I-II in the to to with the indicating the of the I-II not in cells to the domain of with that of using of the were via We previously a detailed of the for of the wild type and calcium channels in cells and their via (34Spaetgens R.L. Zamponi G.W. J. Biol. Chem. 1999; 274: Full Text Full Text PDF PubMed Scopus Google Scholar). the and tetraethylammonium with tetraethylammonium and cesium methanesulfonate 9 9 with tetraethylammonium the of inactivation were the of to and series to voltage were of mV mV for α1E and other chimeras which more to various using However, to inactivation a a to of inactivation the of that inactivated a of and to the of inactivation. were using and inactivation and voltage were using the R.L. Zamponi G.W. J. Biol. Chem. 1999; 274: Full Text Full Text PDF PubMed Scopus Google Scholar). are in in the of and were We previously that wild type α1C and α1E channels in their inactivation (34Spaetgens R.L. Zamponi G.W. J. Biol. Chem. 1999; 274: Full Text Full Text PDF PubMed Scopus Google Scholar). of our we our tetraethylammonium and to a of 9 9 which we to more to the inactivation of the wild type channels our the inactivation of wild type α1C and α1E channels, with and in the the wild type channels different inactivation that the half-inactivation potential of α1E is 60 mV more negative that of the of as the for or the of that has inactivated a of is greater for α1E the in the inactivation of the channels are consistent with our (34Spaetgens R.L. Zamponi G.W. J. Biol. Chem. 1999; 274: Full Text Full Text PDF PubMed Scopus Google a with our the in the were as as those in the half-inactivation of α1C were to mV in the the potential not significantly the inactivation rates in were the substitution of negative ion the or of to account for the However, significantly the inactivation of the channel that the of resulted in a of the inactivation and and an in the of the inactivation. to be for voltage-dependent calcium channels, a calcium channel that multiple domains were in the inactivation process of α1E channels, with domain II and III to the (34Spaetgens R.L. Zamponi G.W. J. Biol. Chem. 1999; 274: Full Text Full Text PDF PubMed Scopus Google Scholar). We that calcium channel inactivation may occur via a mechanism of that underlying inactivation to many of voltage-dependent potassium channels, a process that is to the S6 segments of the channel Aldrich R.W. G. Proc. Natl. Acad. Sci. U. S. A. 1991; PubMed Scopus Google Scholar, M. P. R. J. 1995; PubMed Google Scholar). a of the S6 segments in fast calcium channel we chimeras in which the S6 regions of domains of α1C were replaced the regions of seen in replacement of the II S6 or III S6 segments of α1C with that of α1E the inactivation of α1C to with wild type α1E channels. data that the individual S6 segments in domains II and III are important determinants of calcium channel inactivation. the of domains II and III were we a in which the S6 segments of domains II and III of α1E were into α1C concomitantly replacement not in of the inactivation could the rates that at in the S6 the of a S6 is to many of the more rapid inactivation of the wild type α1E channels, their account for of the voltage dependence with the inactivation rates. the of a S6 in domain II or III of α1E is to rapid inactivation that replacement of only of those S6 segments in be in inactivation. this we and α1E seen in and the chimeras inactivation rates that not significantly those of the wild type α1E at However, substitution of the II S6 and III S6 regions of α1E with those of α1C not significantly slow inactivation the of an region in the α1E sequence that is of inactivation. the region rapid inactivation of we the α1C domain into creating the and α1E-like inactivation However, substitution of most of the α1C domain I-II linker region into this inactivation that the domain I-II linker region of α1E that α1E-like inactivation rates in the α1E the of the domain I-II linker we chimeras and neither in our is an α1C channel the domain I-II linker of α1E rapid inactivation with a are in F. the the inactivation that were significantly those seen with the wild type α1C channels, consistent with our We an that the domain I-II linker the segments of domain II of α1E the domain II S6 and III S6 regions of and to that of the the inactivation that were significantly more rapid those of the wild type not this the that the of of regions in the domain I-II linker or II S6 or III S6 is to rapid the replacement of regions with the of α1C is to slow inactivation We have previously that domains II and III could account for the of in half-inactivation potential between the wild type channels, domains and to a (34Spaetgens R.L. Zamponi G.W. J. Biol. Chem. 1999; 274: Full Text Full Text PDF PubMed Scopus Google Scholar). the of domains II and III could be to the S6 we the half-inactivation of the wild type and calcium channels of the II S6 region of α1E not the half-inactivation and the substitution in α1C resulted in only a in inactivation which a in potential that the domain II S6 region in a to the of inactivation inactivation of the domain III S6 region resulted in more in half-inactivation potential that were not activation potential In of the between the wild type channels, the the S6 regions were that other regions in domains II and III may determine the voltage dependence of inactivation. the and inactivated mV more the wild type α1C channel a potential with the domain I-II of a inactivating of α1E is to the rapid inactivation in an or multiple including that not inactivation rates in of R.L. Zamponi G.W. J. Biol. Chem. 1999; 274: Full Text Full Text PDF PubMed Scopus Google Scholar), are to account for the in voltage dependence of inactivation of the wild type channels. We previously that the calcium channel domains II and III are determinants of the voltage dependence and the of inactivation (34Spaetgens R.L. Zamponi G.W. J. Biol. Chem. 1999; 274: Full Text Full Text PDF PubMed Scopus Google Scholar). of those domains to of the in half-inactivation potential between α1C and and of domains II or III of α1E into the α1Csequence conferred of the rapid inactivation of α1E (34Spaetgens R.L. Zamponi G.W. J. Biol. Chem. 1999; 274: Full Text Full Text PDF PubMed Scopus Google Scholar). we have more identified the regions in the inactivation seen with the α1E sequence in the domain III or I-II linker regions α1E-like inactivation In only α1C sequence in of those regions inactivated consistent with the that the regions are the structural in the of inactivation of the inactivation the of the domain I-II and domain II S6 and III S6 or or data for the chimeras through were and Zamponi (34Spaetgens R.L. Zamponi G.W. J. Biol. Chem. 1999; 274: Full Text Full Text PDF PubMed Scopus Google Scholar). to α1E-like inactivation. the of an α1E sequence in domain II S6 or III S6 or in the domain I-II a which we to be an in our (34Spaetgens R.L. Zamponi G.W. J. Biol. Chem. 1999; 274: Full Text Full Text PDF PubMed Scopus Google Scholar). in a data for the chimeras through were and Zamponi (34Spaetgens R.L. Zamponi G.W. J. Biol. Chem. 1999; 274: Full Text Full Text PDF PubMed Scopus Google Scholar). to α1E-like inactivation. the of an α1E sequence in domain II S6 or III S6 or in the domain I-II a which we to be an in our (34Spaetgens R.L. Zamponi G.W. J. Biol. Chem. 1999; 274: Full Text Full Text PDF PubMed Scopus Google Scholar). of the I-II linker be consistent with the that in this region slow the inactivation of α1A calcium channels (7Bourinet E. Soong T.W. Sutton K. Slaymaker S. Mathews E. Monteil A. Zamponi G.W. Nargeot J. Snutch T.P. Nat. Neurosci. 1999; 2: 407-415Crossref PubMed Scopus (364) Google Scholar, 30Herlitze S. Hockerman G.H. Scheuer T. Catterall W.A. Proc. Natl. Acad. Sci. U. S. A. 1997; 94: 1402-1406Crossref PubMed Scopus (169) Google Scholar). In addition, of the I-II linker regions of α1A to inactivation of the α1A channel T. S. S. Charnet P. J. Biol. Chem. 1999; 274: Full Text Full Text PDF PubMed Scopus Google Scholar). consistent with our in the domain III S6 region have been to inactivation S. Aczel S. Grabner M. Doring F. Berjukow S. Mitterdorfer J. Sinnegger M.J. Striessnig J. Degtiar V.E. Wang Z. Glossmann H. J. Biol. Chem. 1996; 271: 24471-24475Abstract Full Text Full Text PDF PubMed Scopus (75) Google Scholar, R.L. Sinnegger M.J. Glossmann H. S. Striessnig J. J. Biol. Chem. 1998; Full Text Full Text PDF PubMed Scopus Google Scholar). Zhang J.F. Ellinor P.T. Aldrich R.W. Tsien R.W. Nature. 1994; 372: 97-100Crossref PubMed Scopus (177) Google Scholar) the domain S6 region in the fast inactivation process a series of chimeras between α1A and α1E calcium channels, which with our that rapid inactivation not the of α1E domain is replacement of this region with α1C sequence to inactivation. α1E and domain II and III S6 regions and in their domain S6 regions in only in α1A in α1E A. Soong T.W. Snutch T.P. of and and Interestingly, the α1C sequence a in this of domain in our is that an substitution in the domain S6 regions inactivation the of the I-II linker We previously that domains II and III for of the in inactivation seen with the wild type channels (34Spaetgens R.L. Zamponi G.W. J. Biol. Chem. 1999; 274: Full Text Full Text PDF PubMed Scopus Google Scholar). domain III, we a to the S6 indicating that the III S6 region is in the and of the voltage dependence of inactivation. be for the domain I-II linker In the II S6 region the voltage dependence of inactivation being an important for the inactivation Conversely, domain not inactivation contribute to voltage dependence α1E and the structural determinants the rates and voltage dependence of inactivation to be the determinants of inactivation are the mechanism the voltage dependence of inactivation to be more the calcium channel α1 to in of our that fast calcium channel inactivation occur via a mechanism of the inactivation which is to a the S6 segments Refs. Aldrich R.W. G. Proc. Natl. Acad. Sci. U. S. A. 1991; PubMed Scopus Google Scholar and M. P. R. J. 1995; PubMed Google Scholar). data the domain II and III S6 regions with a However, the of the domain I-II linker region a our data are described a in which the I-II linker region a F. J. Scopus Google Scholar) to that for the domain linker of voltage-dependent sodium channels (23Vassilev P. Scheuer T. Catterall W.A. Proc. Natl. Acad. Sci. U. S. A. 1989; 86: 8147Crossref PubMed Scopus (172) Google Scholar, 24Eaholtz G. Scheuer T. Catterall W.A. Neuron. 1994; 12: 1041-1048Abstract Full Text PDF PubMed Scopus (136) Google Scholar) the S6 regions as the docking site for the inactivation that that S6 segments the of the be consistent with a mechanism J. A. R. Science. 1998; PubMed Scopus Google Scholar, R. A. Lee A. Science. 1998; PubMed Scopus Google Scholar, G.A. Y. Jan L.Y. Nature. 1994; PubMed Scopus Google Scholar), may well be that other regions of the channel could be of the docking of the domain I-II linker as the inactivation the previously of in the α1A calcium channel I-II linker (7Bourinet E. Soong T.W. Sutton K. Slaymaker S. Mathews E. Monteil A. Zamponi G.W. Nargeot J. Snutch T.P. Nat. Neurosci. 1999; 2: 407-415Crossref PubMed Scopus (364) Google Scholar, 30Herlitze S. Hockerman G.H. Scheuer T. Catterall W.A. Proc. Natl. Acad. Sci. U. S. A. 1997; 94: 1402-1406Crossref PubMed Scopus (169) Google Scholar) and the of α1A I-II linker to the inactivation of α1A calcium channels. could account for the of the calcium channel which are to to the I-II linker inactivation A. Tomlinson W.J. Soong T.W. Bourinet E. Dubel S.J. Vincent S.R. Snutch T.P. Proc. Natl. Acad. Sci. U. S. A. 1994; 91: 10576-10580Crossref PubMed Scopus (307) Google Scholar, M. M. Mori Y. Tanabe T. Snutch T.P. Nature. 1994; PubMed Scopus Google Scholar, R. A. N. E. 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J. Neural Transm. Suppl. 1994; 43: 1-11PubMed Google Scholar). We T. P. Snutch for the wild type calcium channel

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