Purification and Characterization of Three Inhibitors of Voltage-Dependent K+ Channels from Leiurus Quinquestriatus var. Hebraeus Venom

García, María L.; García‐Calvo, Margarita; Hidalgo, Patricia; Lee, Alice; MacKinnon, Roderick

doi:10.1021/bi00188a012

Cited by 262 publications

(168 citation statements)

References 36 publications

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“…Based on pharmacology of pure populations of Kv channels studied in expression systems, such as the Xenopus oocyte, Kv1.5 and 2.1 meet the pharmacological criteria to be candidate O 2 -responsive and/or E m -regulating Kv channels. Kv2.1 is sensitive to both 4-AP and TEA, but insensitive to CTX (11,22). Kv1.5 is also sensitive to 4-AP and to a lesser extent is inhibited by quinidine and TEA, but it too is insensitive to CTX (Table I).…”

Section: Discussionmentioning

confidence: 99%

“…Kv2.1 (22) and 1.5 (11) are insensitive to Ն 100 nM CTX, although Kv2.1 is somewhat sensitive to TEA (23)(24)(25). Certain members of the Kv1 family were excluded from initial study based on their pharmacology (e.g., Kv1.2 [11] and Kv1.3 and 1.6 [22] are quite sensitive to CTX, Table I). Further basis for selecting Kv2.1 and Kv1.5 for study is evidence of their presence in PASMC (18,(26)(27)(28).…”

Section: Introductionmentioning

confidence: 99%

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Molecular identification of the role of voltage-gated K+ channels, Kv1.5 and Kv2.1, in hypoxic pulmonary vasoconstriction and control of resting membrane potential in rat pulmonary artery myocytes.

Archer¹,

Souil²,

Dinh-Xuan³

et al. 1998

J. Clin. Invest.

371

339

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Hypoxia initiates pulmonary vasoconstriction (HPV) by inhibiting one or more voltage-gated potassium channels (Kv) in the pulmonary artery smooth muscle cells (PASMCs) of resistance arteries. The resulting membrane depolarization increases opening of voltage-gated calcium channels, raising cytosolic Ca 2 ϩ and initiating HPV. There are presently nine families of Kv channels known and pharmacological inhibitors lack the specificity to distinguish those involved in control of resting membrane potential (E m ) or HPV. However, the Kv channels involved in E m and HPV have characteristic electrophysiological and pharmacological properties which suggest their molecular identity. They are slowly inactivating, delayed rectifier currents, inhibited by 4-aminopyridine (4-AP) but insensitive to charybdotoxin. Candidate Kv channels with these traits (Kv1.5 and Kv2.1) were studied. Antibodies were used to immunolocalize and functionally characterize the contribution of Kv1.

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Section: Discussionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

Molecular identification of the role of voltage-gated K+ channels, Kv1.5 and Kv2.1, in hypoxic pulmonary vasoconstriction and control of resting membrane potential in rat pulmonary artery myocytes.

Archer¹,

Souil²,

Dinh-Xuan³

et al. 1998

J. Clin. Invest.

371

339

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“…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%

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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“…Among all Kv channels, the Shaker-related Kv1 channels (Kv1.1-Kv1.7) (1, 2) have been particularly studied, using numerous peptidic blockers isolated from snakes, scorpions, cone snails, and sea anemones (3)(4)(5)(6)(7)(8)(9)(10)(11)(12)(13). These blockers have proved to be useful tools to understand the relationships between potassium currents and potassium channels.…”

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confidence: 99%

Mapping the Functional Anatomy of BgK on Kv1.1, Kv1.2, and Kv1.3

Alessandri‐Haber

Lecoq

Gasparini

et al. 1999

Journal of Biological Chemistry

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BgK is a peptide from the sea anemone Bunodosoma granulifera, which blocks Kv1.1, Kv1.2, and Kv1.3 potassium channels. Using 25 analogs substituted at a single position by an alanine residue, we performed the complete mapping of the BgK binding sites for the three Kv1 channels. These binding sites included three common residues (Ser-23, Lys-25, and Tyr-26) and a variable set of additional residues depending on the particular channel. Shortening the side chain of Lys-25 by taking out the four methylene groups dramatically decreased the BgK affinity to all Kv1 channels tested. However, the analog K25Orn displayed increased potency on Kv1.2, which makes this peptide a selective blocker for Kv1.2 (K D 50-and 300-fold lower than for Kv1.1 and Kv1.3, respectively). BgK analogs with enhanced selectivity could also be made by substituting residues that are differentially involved in the binding to some of the three Kv1 channels. For example, the analog F6A was found to be >500-fold more potent for Kv1.1 than for Kv1.2 and Kv1.3. These results provide new information about the mechanisms by which a channel blocker distinguishes individual channels among closely related isoforms and give clues for designing analogs with enhanced selectivity.

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Purification and Characterization of Three Inhibitors of Voltage-Dependent K+ Channels from Leiurus Quinquestriatus var. Hebraeus Venom

Cited by 262 publications

References 36 publications

Molecular identification of the role of voltage-gated K+ channels, Kv1.5 and Kv2.1, in hypoxic pulmonary vasoconstriction and control of resting membrane potential in rat pulmonary artery myocytes.

Molecular identification of the role of voltage-gated K+ channels, Kv1.5 and Kv2.1, in hypoxic pulmonary vasoconstriction and control of resting membrane potential in rat pulmonary artery myocytes.

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

Mapping the Functional Anatomy of BgK on Kv1.1, Kv1.2, and Kv1.3

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Purification and Characterization of Three Inhibitors of Voltage-Dependent K+ Channels from Leiurus Quinquestriatus var. Hebraeus Venom

Cited by 262 publications

References 36 publications

Molecular identification of the role of voltage-gated K+ channels, Kv1.5 and Kv2.1, in hypoxic pulmonary vasoconstriction and control of resting membrane potential in rat pulmonary artery myocytes.

Molecular identification of the role of voltage-gated K+ channels, Kv1.5 and Kv2.1, in hypoxic pulmonary vasoconstriction and control of resting membrane potential in rat pulmonary artery myocytes.

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

Mapping the Functional Anatomy of BgK on Kv1.1, Kv1.2, and Kv1.3

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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