β Subunit Heterogeneity in Neuronal L-type Ca2+Channels

Pichler, Maria; Cassidy, Tara N.; Reimer, Daniel; Haase, Hannelore; Kraus, Richard L.; Ostler, Dominique; Striessnig, Jörg

doi:10.1074/jbc.272.21.13877

Cited by 106 publications

(105 citation statements)

References 36 publications

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“…This antibody was raised against the C terminus of ␤3 and is thought to detect all known human splice variants. The T cell lines expressed two distinct anti-␤3-reactive proteins of 74 Ϯ 2 kDa and 67 Ϯ 4.2 kDa (n ϭ 12), the latter correlating with the reported molecular mass for ␤3 of 67 kDa in neuronal cells (45). The exception was the Hut78 T cell line, which only expressed the 74 kDa protein.…”

Section: L-type Ca 2ϩ Channel Antagonists Partially Inhibit Thapsigarmentioning

confidence: 56%

Non-voltage-gated L-type Ca2+ Channels in Human T Cells

Stokes¹,

Gordon²,

Grafton

2004

Journal of Biological Chemistry

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In T lymphocytes, engagement of the antigen receptor leads to a biphasic Ca 2؉ flux consisting of a mobilization of Ca 2؉ from intracellular stores followed by a lower but sustained elevation that is dependent on extracellular Ca 2؉ . The prolonged Ca 2؉ flux is required for activation of transcription factors and for subsequent activation of the T cell. Ca 2؉ influx requires as yet unidentified Ca 2؉ channels, which potentially play a role in T cell activation. Here we present evidence that human T cells express a non-voltage-gated Ca 2؉ channel related to L-type voltage-gated Ca 2؉ channels. Drugs that block classical L-type channels inhibited the initial phase of the antigen receptor-induced Ca 2؉ flux and could also inhibit the sustained phase of the Ca 2؉ signal suggesting a role for the L-type Ca 2؉ channel in antigen receptor signaling. T cells expressed transcripts for the ␣ 1 1.2 and ␣ 1 1.3 pore-forming subunits of L-type voltage-gated Ca 2؉ channels and transcripts for all four known ␤-subunits including several potential new splice variants. Jurkat T leukemia cells expressed a small amount of full-length ␣ 1 1.2 protein but the dominant form was a truncated protein identical in size to a truncated ␣ 1 1.2 protein known to be expressed in B lymphocytes. They further expressed a truncated form of the ␣ 1 1.3 subunit and auxiliary ␤1-and ␤3-subunit proteins. Our data strongly suggest that functional but non-voltage-gated L-type Ca 2؉ channels are expressed at the plasma membrane in T cells and play a role in the antigen receptor-mediated Ca 2؉ flux in these cells.

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Section: L-type Ca 2ϩ Channel Antagonists Partially Inhibit Thapsigarmentioning

confidence: 56%

Non-voltage-gated L-type Ca2+ Channels in Human T Cells

Stokes¹,

Gordon²,

Grafton

2004

Journal of Biological Chemistry

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“…2C). This band was identified as the skeletal muscle ␤ 1a homolog of zebrafish based on the following evidence: It was the exclusive protein labeled in pure muscle preparations from normal adult zebrafish, its size agrees with the published molecular mass of rabbit ␤ 1a (52-56 kDa) (23), as well as with the calculated M r for zebrafish ␤ 1a (57 kDa), and it is clearly apart from the 62-to 88-kDa range of ␤ 1b -␤ 4 (23). The higher molecular mass band found in the tail preparations from larvae most likely represents a homologue of another ␤ isoform expressed in neuronal or smooth muscle tissue present in this preparation.…”

Section: ) Statistical Significance Was Determined By Using the ⌬Cmentioning

confidence: 85%

“…2 A) revealed two specific bands at 55 and 62 kDa. Both bands could be completely blocked by antigen preincubation of the antibody (23). Most importantly, the 55-kDa band was absent in preparations from relaxed larvae (Fig.…”

Section: ) Statistical Significance Was Determined By Using the ⌬Cmentioning

confidence: 87%

The β _1a subunit is essential for the assembly of dihydropyridine-receptor arrays in skeletal muscle

Schredelseker

Biase

Obermair

et al. 2005

Proc. Natl. Acad. Sci. U.S.A.

136

164

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Homozygous zebrafish of the mutant relaxed (red ts25 ) are paralyzed and die within days after hatching. A significant reduction of intramembrane charge movements and the lack of depolarizationinduced but not caffeine-induced Ca 2؉ transients suggested a defect in the skeletal muscle dihydropyridine receptor (DHPR). Sequencing of DHPR cDNAs indicated that the ␣1S subunit is normal, whereas the ␤1a subunit harbors a single point mutation resulting in a premature stop. Quantitative RT-PCR revealed that the mutated gene is transcribed, but Western blot analysis and immunocytochemistry demonstrated the complete loss of the ␤1a protein in mutant muscle. Thus, the immotile zebrafish relaxed is a ␤1a-null mutant. Interestingly, immunocytochemistry showed correct triad targeting of the ␣1S subunit in the absence of ␤1a. Freeze-fracture analysis of the DHPR clusters in relaxed myotubes revealed an Ϸ2-fold reduction in cluster size with a normal density of DHPR particles within the clusters. Most importantly, DHPR particles in the junctional membranes of the immotile zebrafish mutant relaxed entirely lacked the normal arrangement in arrays of tetrads. Thus, our data indicate that the lack of the ␤1a subunit does not prevent triad targeting of the DHPR ␣1S subunit but precludes the skeletal muscle-specific arrangement of DHPR particles opposite the ryanodine receptor (RyR1). This defect properly explains the complete deficiency of skeletal muscle excitationcontraction coupling in ␤1-null model organisms.calcium channels ͉ excitation-contraction coupling ͉ tetrads ͉ zebrafish E xcitation-contraction (EC) coupling is understood as the signal transduction process connecting membrane depolarization to the contraction of muscle cells. This process is initiated by the concerted action of two Ca 2ϩ channels, the plasmalemmal voltage-gated dihydropyridine receptor (DHPR) and the sarcoplasmic reticulum (SR) ryanodine receptor (RyR). In junctions of the SR with the plasma membrane (peripheral couplings) or with the transverse tubules (triads), membrane depolarization is sensed by the DHPR, which then triggers RyR opening and Ca 2ϩ release from the SR. In skeletal muscle cells, this signaltransduction is independent of Ca 2ϩ influx through the DHPR (1) but depends on protein-protein interaction between the DHPR and the RyR1 (2, 3). This physical coupling requires the coordinated arrangement of DHPRs and RyR1s in the junctions. In skeletal muscle triads and peripheral couplings, groups of four DHPRs (tetrads) are arranged in orthogonal arrays matching the opposing RyR1 arrays (4). Formation of DHPR tetrads requires the presence of RyR1.The skeletal muscle DHPR complex is composed of the voltage-sensing and pore-forming ␣ 1S subunit and the auxiliary subunits ␤ 1a , ␣ 2 ␦-1, and ␥ (5). Targeted deletions of the ␣ 2 ␦-1 and ␥ subunits do not critically interfere with EC coupling function (6, 7). In contrast, ␣ 1S and ␤ 1a subunit null-mutant mice display a lack of EC coupling and, thus, lethal muscle paralysis (8, 9). Although failure o...

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“…The ␤ subunits are also critical for assembly of the channel complex (18), correct plasma membrane targeting (19,20), and stimulation of channel activity (21). A number of potential ␣1-␤ combinations are likely to form a Cav channel complex (22), and, among these, the ␤4 and ␤3 subunits are key subunits that associate with Cav1 channels (23)(24)(25).…”

Section: Depolarization In Cav Channel Opening In T Cells T Cell Recmentioning

confidence: 99%

Critical role for the β regulatory subunits of Cav channels in T lymphocyte function

Badou¹,

Jha²,

Matza³

et al. 2006

Proc. Natl. Acad. Sci. U.S.A.

147

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Calcium ion is a universal signaling intermediate, which is known to control various biological processes. In excitable cells, voltagegated calcium channels (Cav) are the major route of calcium entry and regulate multiple functions such as contraction, neurotransmitter release, and gene transcription. Here we show that T lymphocytes, which are nonexcitable cells, express both regulatory ␤ and pore-forming Cav1 ␣1 subunits of Cav channels, and we provide genetic evidence for a critical role of the Cav ␤3 and Cav ␤4 regulatory subunits in T lymphocyte function. Cav ␤-deficient T lymphocytes fail to acquire normal functions, and they display impairment in the T cell receptor-mediated calcium response, nuclear factor of activated T cells activation, and cytokine production. In addition, unlike in excitable cells, our data suggest a minimal physiological role for depolarization in Cav channel opening in T cells. T cell receptor stimulation induces only a small depolarization of T cells, and artificial depolarization of T cells using KCl does not lead to calcium entry. These observations suggest that the Cav channels expressed by T cells have adopted novel regulation͞gating mechanisms.C alcium ion plays critical and specific roles in various T cell functions, including activation, differentiation, proliferation, and cytokine production (1, 2). In T lymphocytes, ligation of the T cell receptor (TCR) by antigen leads to the release of calcium from intracellular stores, triggering the calcium release-activated calcium current (3), and a potential candidate for calcium release-activated calcium current channel was recently reported (4-6). But the complexity of the calcium response in T cells suggests the expression of more than one plasma membrane calcium channel. Although it is established that, in excitable cells, Cav channels constitute the major route of calcium entry (7), the functional presence of the Cav1 channels in T lymphocytes has been suggested (8-13) but has remained controversial because of the lack of a reliable and specific loss-of-function approach.Cav ␤ subunits are cytoplasmic proteins that strongly regulate Cav channels through direct interaction with pore-forming ␣1 subunits (14-17). The ␤ subunits are also critical for assembly of the channel complex (18), correct plasma membrane targeting (19,20), and stimulation of channel activity (21). A number of potential ␣1-␤ combinations are likely to form a Cav channel complex (22), and, among these, the ␤4 and ␤3 subunits are key subunits that associate with Cav1 channels (23-25).A spontaneous mutation named lethargic, which arose in the mouse inbred strain BALB͞cGn in 1962, is recognizable in homozygous mice at 2 weeks of age by the onset of ataxia, seizures, and lethargic behavior (26,27). These mice also exhibit a generalized immunological disorder including defective cell-mediated immune responses (28). It has been reported, using a positional cloning approach, that this syndrome was the result of a mutation of the Cav ␤4 subunit gene (29). This mutatio...

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β Subunit Heterogeneity in Neuronal L-type Ca2+Channels

Cited by 106 publications

References 36 publications

Non-voltage-gated L-type Ca2+ Channels in Human T Cells

Non-voltage-gated L-type Ca2+ Channels in Human T Cells

The β _1a subunit is essential for the assembly of dihydropyridine-receptor arrays in skeletal muscle

Critical role for the β regulatory subunits of Cav channels in T lymphocyte function

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β Subunit Heterogeneity in Neuronal L-type Ca2+Channels

Cited by 106 publications

References 36 publications

Non-voltage-gated L-type Ca2+ Channels in Human T Cells

Non-voltage-gated L-type Ca2+ Channels in Human T Cells

The β 1a subunit is essential for the assembly of dihydropyridine-receptor arrays in skeletal muscle

Critical role for the β regulatory subunits of Cav channels in T lymphocyte function

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The β _1a subunit is essential for the assembly of dihydropyridine-receptor arrays in skeletal muscle