T Cell Receptor Mediated Calcium Entry Requires Alternatively Spliced Cav1.1 Channels

Overview

Journal PLoS One

Specialties General Medicine
Science

Date 2016 Jan 28

PMID 26815481

Citations 8

Authors

Didi Matza

Abdallah Badou

Kathryn G Klemic

Judith Stein

Usha Govindarajulu

Monica J Nadler

Jean-Pierre Kinet

Amnon Peled

Oz M Shapira

Leonard K Kaczmarek

Richard A Flavell

Affiliations

Soon will be listed here.

Abstract

The process of calcium entry in T cells is a multichannel and multi-step process. We have studied the requirement for L-type calcium channels (Cav1.1) α1S subunits during calcium entry after TCR stimulation. High expression levels of Cav1.1 channels were detected in activated T cells. Sequencing and cloning of Cav1.1 channel cDNA from T cells revealed that a single splice variant is expressed. This variant lacks exon 29, which encodes the linker region adjacent to the voltage sensor, but contains five new N-terminal exons that substitute for exons 1 and 2, which are found in the Cav1.1 muscle counterpart. Overexpression studies using cloned T cell Cav1.1 in 293HEK cells (that lack TCR) suggest that the gating of these channels was altered. Knockdown of Cav1.1 channels in T cells abrogated calcium entry after TCR stimulation, suggesting that Cav1.1 channels are controlled by TCR signaling.

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References

Gelfand E, Cheung R, Grinstein S, Mills G . Characterization of the role for calcium influx in mitogen-induced triggering of human T cells. Identification of calcium-dependent and calcium-independent signals. Eur J Immunol. 1986; 16(8):907-12. DOI: 10.1002/eji.1830160806. View

Matza D, Badou A, Kobayashi K, Goldsmith-Pestana K, Masuda Y, Komuro A . A scaffold protein, AHNAK1, is required for calcium signaling during T cell activation. Immunity. 2008; 28(1):64-74. PMC: 2350190. DOI: 10.1016/j.immuni.2007.11.020. View

Catterall W . Structure and regulation of voltage-gated Ca2+ channels. Annu Rev Cell Dev Biol. 2000; 16:521-55. DOI: 10.1146/annurev.cellbio.16.1.521. View

Komuro A, Masuda Y, Kobayashi K, Babbitt R, Gunel M, Flavell R . The AHNAKs are a class of giant propeller-like proteins that associate with calcium channel proteins of cardiomyocytes and other cells. Proc Natl Acad Sci U S A. 2004; 101(12):4053-8. PMC: 384694. DOI: 10.1073/pnas.0308619101. View

Winslow M, Neilson J, Crabtree G . Calcium signalling in lymphocytes. Curr Opin Immunol. 2003; 15(3):299-307. DOI: 10.1016/s0952-7915(03)00050-5. View

Luo D, Nakazawa M, Yoshida Y, Cai J, Imai S . Effects of three different Ca(2+) pump ATPase inhibitors on evoked contractions in rabbit aorta and activities of Ca(2+) pump ATPases in porcine aorta. Gen Pharmacol. 2000; 34(3):211-20. DOI: 10.1016/s0306-3623(00)00064-1. View

Lewis R . The molecular choreography of a store-operated calcium channel. Nature. 2007; 446(7133):284-7. DOI: 10.1038/nature05637. View

Berridge M . Cell signalling. A tale of two messengers. Nature. 1993; 365(6445):388-9. DOI: 10.1038/365388a0. View

Kotturi M, Hunt S, Jefferies W . Roles of CRAC and Cav-like channels in T cells: more than one gatekeeper?. Trends Pharmacol Sci. 2006; 27(7):360-7. DOI: 10.1016/j.tips.2006.05.007. View

10.

Minor Jr D, Findeisen F . Progress in the structural understanding of voltage-gated calcium channel (CaV) function and modulation. Channels (Austin). 2010; 4(6):459-74. PMC: 3018750. DOI: 10.4161/chan.4.6.12867. View

11.

Kotturi M, Jefferies W . Molecular characterization of L-type calcium channel splice variants expressed in human T lymphocytes. Mol Immunol. 2005; 42(12):1461-74. DOI: 10.1016/j.molimm.2005.01.014. View

12.

Jha M, Badou A, Meissner M, McRory J, Freichel M, Flockerzi V . Defective survival of naive CD8+ T lymphocytes in the absence of the beta3 regulatory subunit of voltage-gated calcium channels. Nat Immunol. 2009; 10(12):1275-82. PMC: 2785134. DOI: 10.1038/ni.1793. View

13.

Tang Z, Yarotskyy V, Wei L, Sobczak K, Nakamori M, Eichinger K . Muscle weakness in myotonic dystrophy associated with misregulated splicing and altered gating of Ca(V)1.1 calcium channel. Hum Mol Genet. 2011; 21(6):1312-24. PMC: 3284119. DOI: 10.1093/hmg/ddr568. View

14.

Rubinson D, Dillon C, Kwiatkowski A, Sievers C, Yang L, Kopinja J . A lentivirus-based system to functionally silence genes in primary mammalian cells, stem cells and transgenic mice by RNA interference. Nat Genet. 2003; 33(3):401-6. DOI: 10.1038/ng1117. View

15.

Kotturi M, Carlow D, Lee J, Ziltener H, Jefferies W . Identification and functional characterization of voltage-dependent calcium channels in T lymphocytes. J Biol Chem. 2003; 278(47):46949-60. DOI: 10.1074/jbc.M309268200. View

16.

Savignac M, Badou A, Moreau M, Leclerc C, Guery J, Paulet P . Protein kinase C-mediated calcium entry dependent upon dihydropyridine sensitive channels: a T cell receptor-coupled signaling pathway involved in IL-4 synthesis. FASEB J. 2001; 15(9):1577-9. DOI: 10.1096/fj.00-0733fje. View

17.

Omilusik K, Priatel J, Chen X, Wang Y, Xu H, Choi K . The Ca(v)1.4 calcium channel is a critical regulator of T cell receptor signaling and naive T cell homeostasis. Immunity. 2011; 35(3):349-60. DOI: 10.1016/j.immuni.2011.07.011. View

18.

Feske S . Calcium signalling in lymphocyte activation and disease. Nat Rev Immunol. 2007; 7(9):690-702. DOI: 10.1038/nri2152. View

19.

Gwack Y, Srikanth S, Oh-Hora M, Hogan P, Lamperti E, Yamashita M . Hair loss and defective T- and B-cell function in mice lacking ORAI1. Mol Cell Biol. 2008; 28(17):5209-22. PMC: 2519726. DOI: 10.1128/MCB.00360-08. View

20.

Gallo E, Cante-Barrett K, Crabtree G . Lymphocyte calcium signaling from membrane to nucleus. Nat Immunol. 2005; 7(1):25-32. DOI: 10.1038/ni1295. View