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- Coleman, N. et al. (2014) Mol. Pharmacol. 86, 342.
- Alomone Labs SKA-121 activates KCa3.1 (SK4) currents in stably transfected 293T cells.A. Representative time course of KCa3.1 current at 0 mV, recorded using whole-cell patch-clamp. Membrane potential was held at -80 mV, a 150 ms voltage ramp from -120 mV to +60 mV was applied every 10 sec. Current was activated at low nanomolar [Ca2+]in by application of 1 µM and 10 µM SKA-121 (#S-245), as indicated. B. Superimposed traces of KCa3.1 current following application of 1 µM and 10 µM SKA-121, taken from the recording in A.
KCa3.1 is a calcium-activated K+ channel. KCa2/3 channels are voltage-independent and share a Ca2+/calmodulin-mediated gating mechanism1.
KCa3.1 and KCa2 channels are expressed in cells and enable them to hyperpolarize in order to regulate Ca2+ influx through inward rectifier Ca2+ channels, pass on hyperpolarization through gap junctions, or regulate firing frequency by preventing an untimely or premature action potential initiation2. Pharmacological activation of KCa channels has therefore been suggested as a treatment for various diseases. The different specific activities of KCa2 and KCa3.1 channels create a difference between the activators of these two types of channels. KCa2 activators can potentially reduce neuronal excitability in central nervous system disorders like epilepsy and ataxia. KCa3.1 activators could be useful as endothelial targeted antihypertensives and to enhance fluid secretion in the airways in cystic fibrosis3,4.
The positive-gating modulators used until today have low selectivity and affect both KCa2 and KCa3.1, making it impossible to differentiate the phenotypes of these two receptors. To avoid KCa2 channel-mediated side effects, it is highly desirable to identify selective KCa3.1 activators that could be used as pharmacological tools to further dissect the in vivo role of KCa3.1 in blood pressure control and to help determine whether KCa3.1 activators could eventually be developed into a new class of endothelial-targeted antihypertensives. SKA-121 (5-methylnaphtho[2,1-d]oxazol-2-amine), a compound generated through an isosteric replacement approach, activates KCa3.1 with an EC50 of 111 nM, exhibits 40- to 80-fold selectivity over the three KCa2 channels and lowers blood pressure in mice as determined by telemetry without exerting KCa2 channel-mediated effects on HR5.
SKA-121 (#S-245) is a highly pure, synthetic, and biologically active compound.