Tumor growth rate varies with age in lethargic mutant BALB/cGnDu mice

Morrison, David G.; Moyer, Mary Pat; Dung, Houchi; Rogers, William E.; Moyer, Rex C.

doi:10.1016/0145-305x(84)90050-8

Cited by 3 publications

(2 citation statements)

References 18 publications

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“…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).…”

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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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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“…Neither full-length nor truncated β4 protein is expressed in the mutant mice (49). Interestingly, these mice experience an immunological disorder, including a defect in their cell-mediated immune response (50). β regulatory subunits, β1–β4, are crucial for normal Ca v channel function (51), since they are required for the expression of functional channels at the plasma membrane (52), and modulate their biophysical properties by interacting with pore-forming α subunit (51).…”

Section: Role Of β Regulatory Subunits and Cav1 Channels In T Cell Acmentioning

confidence: 99%

Emerging Roles of L-Type Voltage-Gated and Other Calcium Channels in T Lymphocytes

et al. 2013

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† Abdallah Badou and Mithilesh K. Jha have contributed equally to this work.In T lymphocytes, calcium ion controls a variety of biological processes including development, survival, proliferation, and effector functions. These distinct and specific roles are regulated by different calcium signals, which are generated by various plasma membrane calcium channels. The repertoire of calcium-conducting proteins in T lymphocytes includes store-operated CRAC channels, transient receptor potential channels, P2X channels, and L-type voltage-gated calcium (Ca v 1) channels. In this paper, we will focus mainly on the role of the Ca v 1 channels found expressed by T lymphocytes, where these channels appear to operate in aT cell receptor stimulation-dependent and voltage sensor independent manner. We will review their expression profile at various differentiation stages of CD4 and CD8 T lymphocytes. Then, we will present crucial genetic evidence in favor of a role of these Ca v 1 channels and related regulatory proteins in both CD4 and CD8T cell functions such as proliferation, survival, cytokine production, and cytolysis. Finally, we will provide evidence and speculate on how these voltage-gated channels might function in the T lymphocyte, a non-excitable cell.

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Requirement of Voltage-Gated Calcium Channel β ₄ Subunit for T Lymphocyte Functions

Badou

Basavappa

Desai

et al. 2005

Science

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Calcium is known to play vital roles in diverse physiological processes, and it is known that voltage-gated calcium channels (Cav) mediate calcium influx in excitable cells. However, no consensus exists on the molecular identity of the calcium channels present in nonexcitable cells such as T lymphocytes. Here, we demonstrate that T lymphocytes express both regulatory beta4 and poreforming Cav1 alpha1 subunits of Cav channels. Cav beta4-mutant T lymphocytes fail to acquire normal functions and display impairment in the calcium response, activation of the transcription factor NFAT, and cytokine production. Although Cav1 channels of lymphocytes retain their voltage dependency, T cell receptor stimulation dramatically increases channel opening, providing a new mechanism for calcium entry in lymphocytes.

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Tumor growth rate varies with age in lethargic mutant BALB/cGnDu mice

Cited by 3 publications

References 18 publications

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

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

Emerging Roles of L-Type Voltage-Gated and Other Calcium Channels in T Lymphocytes

Requirement of Voltage-Gated Calcium Channel β ₄ Subunit for T Lymphocyte Functions

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Tumor growth rate varies with age in lethargic mutant BALB/cGnDu mice

Cited by 3 publications

References 18 publications

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

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

Emerging Roles of L-Type Voltage-Gated and Other Calcium Channels in T Lymphocytes

Requirement of Voltage-Gated Calcium Channel β 4 Subunit for T Lymphocyte Functions

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Requirement of Voltage-Gated Calcium Channel β ₄ Subunit for T Lymphocyte Functions