WIN 17317-3 blocks Ca2+-activated K+ channels and enhances motility of guinea-pig detrusor muscle

Vianna‐Jorge, Rosane; Oliveira, Cyntia Ferreira de; Ponte, Cristiano G.; Suarez‐Kurtz, Guilherme

doi:10.1016/s0014-2999(01)01347-4

Cited by 3 publications

(1 citation statement)

References 12 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…Later it was also shown to block Na + and Ca 2+ -activated K + channels [76,77]. CP-319, 818, a closely related compound [58], was effective on Kv1.3 channels at similar concentrations, binding with 1:1 stoichiometry.…”

Section: Small-molecule Inhibitors Of Kv13 and Ikca1 Channelsmentioning

confidence: 99%

K+ Channel Blockers: Novel Tools to Inhibit T Cell Activation Leading to Specific Immunosuppression

Panyi

Possani²,

Vega³

et al. 2006

CPD

View full text Add to dashboard Cite

During the last two decades since the identification and characterization of T cell potassium channels great advances have been made in the understanding of the role of these channels in T cell functions, especially in antigen-induced activation. Their limited tissue distribution and the recent discovery that different T cell subtypes carrying out distinct immune functions show specific expression levels of these channels have made T cell potassium channels attractive targets for immunomodulatory drugs. Many toxins of various animal species and a structurally diverse array of small molecules inhibiting these channels with varying affinity and selectivity were found and their successful use in immunosuppression in vivo was also demonstrated. Better understanding of the topological differences between potassium channel pores, detailed knowledge of toxin and small-molecule structures and the identification of the binding sites of blocking compounds make it possible to improve the selectivity and affinity of the lead compounds by introducing modifications based on structural information. In this review the basic properties and physiological roles of the voltage-gated Kv1.3 and the Ca2+-activated IKCa1 potassium channels are discussed along with an overview of compounds inhibiting these channels and approaches aiming at producing more efficient modulators of immune functions for the treatment of diseases like sclerosis multiplex and type I diabetes.

show abstract

Section: Small-molecule Inhibitors Of Kv13 and Ikca1 Channelsmentioning

confidence: 99%

K+ Channel Blockers: Novel Tools to Inhibit T Cell Activation Leading to Specific Immunosuppression

Panyi

Possani²,

Vega³

et al. 2006

CPD

View full text Add to dashboard Cite

show abstract

Large-conductance, calcium-activated potassium channels: Structural and functional implications

Ghatta¹,

Nimmagadda²,

Xu³

et al. 2006

Pharmacology & Therapeutics

296

259

View full text Add to dashboard Cite

Potassium Channels in T Lymphocytes

Vianna‐Jorge

Suarez‐Kurtz

2004

BioDrugs

View full text Add to dashboard Cite

Human peripheral blood T lymphocytes possess two types of K(+) channels: the voltage-gated Kv1.3 and the calcium-activated IKCa1 channels. The use of peptidyl inhibitors of Kv1.3 and IKCa1 indicated that these channels are involved in the maintenance of membrane potential and that they play a crucial role in Ca(2+) signaling during T-cell activation. Thus, in vitro blockade of Kv1.3 and IKCa1 leads to inhibition of cytokine production and lymphocyte proliferation. These observations prompted several groups of investigators in academia and pharmaceutical companies to characterize the expression of Kv1.3 and IKCa1 in different subsets of human T lymphocytes and to evaluate their potential as novel targets for immunosuppression. Recent in vivo studies showed that chronically activated T lymphocytes involved in the pathogenesis of multiple sclerosis present unusually high expression of Kv1.3 channels and that the treatment with selective Kv1.3 inhibitors can either prevent or ameliorate the symptoms of the disease. In this model of multiple sclerosis, blockade of IKCa1 channels had no effect alone, but improved the response to Kv1.3 inhibitors. In addition, the expression of Kv1.3 and IKCa1 channels in human cells is very restricted, which makes them attractive targets for a more cell-specific and less harmful action than what is typically obtained with classical immunosuppressants. Studies using high-throughput toxin displacement, (86)Rb-efflux screening or membrane potential assays led to the identification of non-peptidyl small molecules with high affinity for Kv1.3 or IKCa1 channels. Analysis of structure-function relationships in Kv1.3 and IKCa1 channels helped define the binding sites for channel blockers, allowing the design of a new generation of small molecules with selectivity for either Kv1.3 or IKCa1, which could help the development of new drugs for safer treatment of auto-immune diseases.

show abstract

WIN 17317-3 blocks Ca2+-activated K+ channels and enhances motility of guinea-pig detrusor muscle

Cited by 3 publications

References 12 publications

K+ Channel Blockers: Novel Tools to Inhibit T Cell Activation Leading to Specific Immunosuppression

K+ Channel Blockers: Novel Tools to Inhibit T Cell Activation Leading to Specific Immunosuppression

Large-conductance, calcium-activated potassium channels: Structural and functional implications

Potassium Channels in T Lymphocytes

Contact Info

Product

Resources

About