Correolide and Derivatives Are Novel Immunosuppressants Blocking the Lymphocyte Kv1.3 Potassium Channels

Koo, Gloria C.; Blake, J T; Shah, Kashmira; Staruch, Mary Jo; Dumont, Francis J.; Wunderler, Denise; Sánchez, Manuel; McManus, Owen B.; Sirotina-Meisher, Anna; Fischer, Paul; Boltz, Robert C.; Goetz, Michael; Baker, Robert K.; Bao, Jianming; Kayser, Frank; Rupprecht, Kathleen M.; Parsons, William H.; Tong, Xinchun; Ita, Ida E.; Pivnichny, Jim; Vincent, Stella; Cunningham, Patrick N.; Hora, Donald F.; Feeney, William P.; Kaczorowski, Gregory J.; Springer, Martin S.

doi:10.1006/cimm.1999.1569

Cited by 83 publications

(110 citation statements)

References 20 publications

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“…These data illustrate that Kv1.3 up-regulation during G 1 is a prerequisite for G 1 ͞S transition. In fact, Kv1.3 has been implicated in the proliferation of other cell types (24,31,32).…”

Section: Discussionmentioning

confidence: 99%

“…To examine whether I K expressed by NG2 ϩ OPs in the SVZ͞developing white matter contain or comprise Kv1.3 subunits, we studied the effects of the Kv1.3 channel blockers, r-agitoxin (AgTx) and r-margatoxin (MgTx), at concentrations shown to be selective for Kv1.3-containing channels (21)(22)(23)(24). Both of these toxins only partially inhibited I K in these cells (Fig.…”

Section: Ops In Acutely Isolated Slices Display Ik That Are Partiallymentioning

confidence: 99%

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Regulation of Kv1 subunit expression in oligodendrocyte progenitor cells and their role in G ₁ /S phase progression of the cell cycle

Chittajallu

Chen

Wang

et al. 2002

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

159

146

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Proliferative oligodendrocyte progenitor cells (OPs) express large, delayed outward-rectifying K ؉ currents (IK), whereas nondividing immature and mature oligodendrocytes display much smaller I K. Here, we show that up-regulation of IK occurs in G1 phase of the cell cycle in purified cultured OPs and is the result of an RNA synthesis-dependent, selective increase of the K ؉ channel subunit proteins Kv1.3 and Kv1.5. In oligodendrocyte cells acutely isolated from developing rat brain, a decrease of cyclin D expression is observed as these cells mature along their lineage. This is accompanied by a decrease in Kv1.3 and Kv1.5 subunit expression, suggesting a role for these subunits in the proliferative potential of OPs in situ. IK expressed in OPs in subventricular zone and developing white matter in acutely isolated slice preparations were selectively blocked by antagonists of Kv1.3, illustrating the functional presence of this subunit in situ. Interestingly, Kv1.3 block inhibited S-phase entry of both purified OPs in culture and in tissue slice cultures. Thus, we employ both in vitro and in situ experimental approaches to show that (i) RNA-dependent synthesis of Kv1.3 and Kv1.5 subunit proteins occurs in G 1 phase of the OP cell cycle and is responsible for the observed increase in I K, and (ii) currents through Kv1.3-containing channels play a crucial role in G 1͞S transition of proliferating OPs. O ligodendrocytes, a major class of macroglia, are responsible for myelination in the central nervous system and primarily originate from highly proliferative oligodendrocyte precursor cells (OPs) in a spatially restricted central nervous system area termed the subventricular zone (SVZ; refs. 1 and 2). Under the influence of extrinsic trophic signals (3, 4), OPs migrate, proliferate, and the majority differentiate (by means of a number of intermediate cell stages) into myelinating oligodendrocytes.A correlation exists between expression of the delayed, outward-rectifying voltage-gated K ϩ currents (I K ) and the proliferative potential of oligodendrocyte lineage cells (5-9). Proliferating OPs possess large I K , whereas postmitotic oligodendrocytes do not express such currents (5-9). However, few studies have attempted to identify the cellular mechanisms responsible for these K ϩ channel changes in OPs. Furthermore, although the functional properties of these channels indicate that they are composed of subunits of the Kv1 subfamily (9, 10), the molecular identity of the K ϩ channel subunits involved in the developmental alterations of K ϩ channel expression in OPs has not been extensively analyzed.We have previously used a cell culture model system that allows OPs to be synchronized in a nonproliferative state (G 0 ) and be induced to enter the cell cycle upon mitogen treatment (11,12). By using this approach, we have previously shown that mitogen-induced entry of OPs into the cell cycle is accompanied by a marked increase in I K . § In the present study, we take further advantage of this culture system to: (i) analyze ...

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“…These data illustrate that Kv1.3 up-regulation during G 1 is a prerequisite for G 1 ͞S transition. In fact, Kv1.3 has been implicated in the proliferation of other cell types (24,31,32).…”

Section: Discussionmentioning

confidence: 99%

Section: Ops In Acutely Isolated Slices Display Ik That Are Partiallymentioning

confidence: 99%

Regulation of Kv1 subunit expression in oligodendrocyte progenitor cells and their role in G ₁ /S phase progression of the cell cycle

Chittajallu

Chen

Wang

et al. 2002

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

159

146

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“…Earlier studies showed that the Kv1.3 blockers margatoxin, correolide, and kaliotoxin suppressed delayed-type hypersensitivity (DTH) in miniswine and rats (5,69,70). Based on these results, investigators in the field (5, 71) concluded that Kv1.3 blockers inhibited the primary immune response and caused generalized immunosuppression.…”

Section: Cd27mentioning

confidence: 99%

“…In proof-of-concept studies in rats, Kv1.3 blockers have been shown to ameliorate adoptive experimental autoimmune encephalomyelitis induced by myelin-specific memory T cells (16,70), a model for MS, and to prevent inflammatory bone resorption in experimental periodontal disease caused mainly by memory cells (81). Several small-molecule Kv1.3 inhibitors with nanomolar potency have been developed over the last decade (WIN-17317, CP-339818, U.K.-78,282, correolide, trans-N-propylcarbamoyloxy-PAC, sulfamidebenzamidoindanes, tetraphenylporphyrins, dichlorophenylpyrazolopyrimidines, chalcones, and Psora-4 (6,7,31,69,82,83)), and the continuing development of more selective and potent Kv1.3 blockers may make Kv1.3-based immunomodulation for autoimmune disorders a reality.…”

Section: Cd27mentioning

confidence: 99%

K+ Channel Expression during B Cell Differentiation: Implications for Immunomodulation and Autoimmunity

Wulff

Knaus

Pennington

et al. 2004

The Journal of Immunology

175

189

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Using whole-cell patch-clamp, fluorescence microscopy and flow cytometry, we demonstrate a switch in potassium channel expression during differentiation of human B cells from naive to memory cells. Naive and IgD+CD27+ memory B cells express small numbers of the voltage-gated Kv1.3 and the Ca2+-activated intermediate-conductance IKCa1 channel when quiescent, and increase IKCa1 expression 45-fold upon activation with no change in Kv1.3 levels. In contrast, quiescent class-switched memory B cells express high levels of Kv1.3 (∼2000 channels/cell) and maintain their Kv1.3high expression after activation. Consistent with their channel phenotypes, proliferation of naive and IgD+CD27+ memory B cells is suppressed by the specific IKCa1 inhibitor TRAM-34 but not by the potent Kv1.3 blocker Stichodactyla helianthus toxin, whereas the proliferation of class-switched memory B cells is suppressed by Stichodactyla helianthus toxin but not TRAM-34. These changes parallel those reported for T cells. Therefore, specific Kv1.3 and IKCa1 inhibitors may have use in therapeutic manipulation of selective lymphocyte subsets in immunological disorders.

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“…Kv1.3 is the primary regulator of Ca 2ϩ signaling in human quiescent T cells. Selective blockade of Kv1.3, but not IKCa1, suppresses mitogenstimulated cytokine production and proliferation of these cells in vitro (14)(15)(16)(17) and the delayed type hypersensitivity response in vivo (6,18,19). Transcriptional up-regulation during mitogenesis results in IKCa1 becoming the main regulator of Ca 2ϩ signaling in human activated lymphocytes, and selective IKCa1 blockade suppresses cytokine production and mitogenesis of preactivated cells (17,20,21).…”

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confidence: 99%

Selective blockade of T lymphocyte K⁺channels ameliorates experimental autoimmune encephalomyelitis, a model for multiple sclerosis

Beeton

Wulff

Barbaria

et al. 2001

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

304

369

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Correolide and Derivatives Are Novel Immunosuppressants Blocking the Lymphocyte Kv1.3 Potassium Channels

Cited by 83 publications

References 20 publications

Regulation of Kv1 subunit expression in oligodendrocyte progenitor cells and their role in G ₁ /S phase progression of the cell cycle

Regulation of Kv1 subunit expression in oligodendrocyte progenitor cells and their role in G ₁ /S phase progression of the cell cycle

K+ Channel Expression during B Cell Differentiation: Implications for Immunomodulation and Autoimmunity

Selective blockade of T lymphocyte K⁺channels ameliorates experimental autoimmune encephalomyelitis, a model for multiple sclerosis

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Correolide and Derivatives Are Novel Immunosuppressants Blocking the Lymphocyte Kv1.3 Potassium Channels

Cited by 83 publications

References 20 publications

Regulation of Kv1 subunit expression in oligodendrocyte progenitor cells and their role in G 1 /S phase progression of the cell cycle

Regulation of Kv1 subunit expression in oligodendrocyte progenitor cells and their role in G 1 /S phase progression of the cell cycle

K+ Channel Expression during B Cell Differentiation: Implications for Immunomodulation and Autoimmunity

Selective blockade of T lymphocyte K+channels ameliorates experimental autoimmune encephalomyelitis, a model for multiple sclerosis

Contact Info

Product

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About

Regulation of Kv1 subunit expression in oligodendrocyte progenitor cells and their role in G ₁ /S phase progression of the cell cycle

Regulation of Kv1 subunit expression in oligodendrocyte progenitor cells and their role in G ₁ /S phase progression of the cell cycle

Selective blockade of T lymphocyte K⁺channels ameliorates experimental autoimmune encephalomyelitis, a model for multiple sclerosis