Mechanism of Cav1.2 channel modulation by the amino terminus of cardiac β2‐subunits

Wiley - Tập 21 Số 7 - Trang 1527-1538 - 2007
Stefan Herzig1,2, Ismail Khan1,2, Dirk Gründemann1,2, Jan Matthes2, A. Ludwig3, Guido Michels4, Uta C. Hoppe1,4, Dipayan Chaudhuri5, Arnold Schwartz6, David T. Yue5, Roger Hullin7
1Center of Molecular MedicineUniversity of CologneCologneGermany
2Department of PharmacologyUniversity of CologneCologneGermany
3Institute of Experimental and Clinical Pharmacology and ToxicologyUniversity Erlangen-NuernbergErlangenGermany
4Internal Medicine IIIUniversity of CologneCologneGermany
5Johns Hopkins University School of MedicineBaltimoreMarylandUSA
6Institute of Molecular Pharmacology and BiophysicsUniversity of CincinnatiCincinnatiOhioUSA
7Department of CardiologySwiss Heart Center BernUniversity HospitalBernSwitzerland

Tóm tắt

ABSTRACTL‐type calcium channels are composed of a pore, α1c (CaV1.2), and accessory β‐ and α2δ‐subunits. The β‐subunit core structure was recently resolved at high resolution, providing important information on many functional aspects of channel modulation. In this study we reveal differential novel effects of five ß2‐subunits isoforms expressed in human heart ( β 2a‐e) on the single L‐type calcium channel current. These splice variants differ only by amino‐terminal length and amino acid composition. Single‐channel modulation by β2‐subunit isoforms was investigated in HEK293 cells expressing the recombinant L‐type ion conducting pore. All β2‐subunits increased open probability, availability, and peak current with a highly consistent rank order (ß2a≈ ß2b>ß2e≈ ß2c>ß2d). We show graded modulation of some transition rates within and between deep‐closed and inactivated states. The extent of modulation correlates strongly with the length of amino‐terminal domains. Two mutant ß2‐subunits that imitate the natural span related to length confirm this conclusion. The data show that the length of amino termini is a relevant physiological mechanism for channel closure and inactivation, and that natural alternative splicing exploits this principle for modulation of the gating properties of calcium channels.—Herzig, S., Khan, I. F. Y., Gründemarin, D., Matthes, J., Ludwig, A., Michels, G., Hoppe, U. C., Chaudhuri, D., Schwartz, A., Yue, D. T., Hullin, R. Mechanism of Cav1.2 channel modulation by the amino terminus of cardiac ß2‐sub‐units. FASEB J. 21, 1527–1538 (2007)

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Tài liệu tham khảo

10.1016/S0896-6273(00)81057-0

10.1126/science.2549640

10.1002/j.1460-2075.1992.tb05126.x

10.1016/S0021-9258(18)46015-2

10.1016/S0021-9258(18)53715-7

10.1042/bst0220483

10.1126/science.2458626

Felix R., 1999, Voltage-dependent Ca2+ channel α2δ auxiliary subunit: structure, function and regulation, Receptors Channels, 6, 351

10.1124/mol.62.3.485

10.1016/S0014-5793(00)01306-5

10.1161/01.RES.86.2.175

10.1113/jphysiol.2002.018515

10.1074/jbc.M211164200

10.1016/0014-5793(94)00938-4

Suh-Kim H., 1996, subunit composition is a major determinant in high affinity binding of aCa2+ channel blocker, Mol. Pharmacol., 50, 1330

10.1161/01.CIR.98.10.969

10.1016/j.bbrc.2003.12.174

10.1161/01.CIR.100.2.155

10.1016/0014-5793(93)80135-H

10.1016/S0006-3495(03)70027-7

10.1152/physiolgenomics.00207.2003

10.1074/jbc.M409523200

10.1023/A:1021989622656

10.1074/jbc.273.4.2361

10.1016/0896-6273(94)90363-8

10.1038/368067a0

10.1016/0014-5793(96)00007-5

10.1085/jgp.200509354

10.1016/S0896-6273(04)00259-4

10.1038/nature02588

10.1016/S0896-6273(04)00250-8

10.1038/nature02641

10.1074/jbc.273.36.23590

10.1016/0896-6273(94)90428-6

10.1523/JNEUROSCI.0067-06.2006

10.1523/JNEUROSCI.17-04-01339.1997

10.1074/jbc.272.16.10408

10.2144/96215rr02

10.1074/jbc.273.52.35222

10.1073/pnas.90.13.6228

10.1124/mol.61.3.682

10.1016/S0006-3495(87)83298-8

10.1016/S0006-3495(91)82069-0

Freise D., 1999, Mutations of calcium channel β subunit genes in mice, Biol. Chem., 380, 897, 10.1515/BC.1999.110

10.1007/BF00196785

10.1016/j.cell.2004.09.011

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Wiley

Tập 21 Số 7

1527-1538

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