Pharmacological gating modulation of small- and intermediate-conductance Ca²⁺-activated K⁺channels (K_Ca2.x and K_Ca3.1)

Switching between persistent firing and depolarization block in individual rat CA1 pyramidal neurons

“…Next, we assessed whether the involvement of M and SK currents in the induction of DB was bi‐directional. Therefore, we enhanced the M or SK current by co‐applying either 10 μM retigabine (Gunthorpe, Large, & Sankar, ; Rundfeldt, ) or 10 μM NS309 (Christophersen & Wulff, ; Pedarzani et al, ) to cells that previously exhibited DB in the Cch‐only condition. During the co‐application of NS309 (SK current enhancer) for 17 min ( SD : 3 min) in addition to Cch (20 μM), none of the eight cells continued to show DB.…”

Ca2+ signalling in fibroblasts and the therapeutic potential of KCa3.1 channel blockers in fibrotic diseases

“…is sensitive to submicromolar Ca 2+ concentrations, with EC 50 values ranging from 100 to 300 nM (Ishii et al, 1997;Neylon et al, 1999 (Devor et al, 1996;Duffy et al, 2004;Pedersen et al, 1999). Importantly, 1-EBIO also activates K Ca 2.1-3 channels at approximately fivefold to 10-fold higher concentrations than the EC 50 of K Ca 3.1, so it is not entirely selective for K Ca 3.1, although it is useful for research purposes (Christophersen & Wulff, 2015). Further K Ca 3.1 positive modu- Singh et al, 2001), an analogue of 1-EBIO but with a potency 10 times greater, as well as NS309 and riluzole derivatives such as SKA-31 (Sankaranarayanan et al, 2009; Figure 2).…”

“…1‐Ethyl‐2‐benzimidazolinone (1‐EBIO) activates heterologously expressed K Ca 3.1 with an EC 50 of 30 μM and achieves maximal K + currents at 100 μM in the presence of 100 nM of free Ca 2+ (Devor et al, ; Duffy et al, ; Pedersen et al, ). Importantly, 1‐EBIO also activates K Ca 2.1–3 channels at approximately fivefold to 10‐fold higher concentrations than the EC 50 of K Ca 3.1, so it is not entirely selective for K Ca 3.1, although it is useful for research purposes (Christophersen & Wulff, ). Further K Ca 3.1 positive modulators include 5,6‐dichloro‐1‐ethyl‐1,3‐dihydro‐2 H ‐benzimidazole‐2‐one (DC‐EBIO; Singh et al, ), an analogue of 1‐EBIO but with a potency 10 times greater, as well as NS309 and riluzole derivatives such as SKA‐31 (Sankaranarayanan et al, ; Figure ).…”

Conditional KCa3.1-transgene induction in murine skin produces pruritic eczematous dermatitis with severe epidermal hyperplasia and hyperkeratosis

“…2) In addition to its function as a K + secreting channel, KCa3.1 activity is known to produce strong membrane hyperpolarization, which in turn potentiates calcium-influx enabling longlasting elevations in [Ca 2+ ] I (for review see: [1,36]). In several cell systems, this elevation of [Ca 2+ ] I has been shown to be required for the sustained initiation of several cellular processes, including proliferation and migration [1,47].…”

“…In addition, high expression of KCa3.1 has been considered a marker of tumor progression for some cancers [3,33,34]. KCa3.1, therefore, can be viewed as a possible driver of disease, and several small molecule inhibitors for this therapeutically attractive target have been developed and tested in pre-clinical animal models [35,36]. The inhibitor, ICA-17043 (Senicapoc), initially intended for the treatment of sickle cell anemia, has been found clinically safe [37] and is currently being considered for drug repurposing for stroke and Alzheimer's disease, two conditions in which KCa3.1 contributes to the pathophysiology [19,38].…”