Long-term effects of sustained SK3 channel activation in the central nervous system

Determine the long-term physiological and pathological consequences of prolonged pharmacological activation of SK3 (KCa2.3) small-conductance calcium-activated potassium channels in the central nervous system, including impacts on neuronal function and safety relevant to therapeutic modulation of SKCa channels.

Background

SK3 channels are widely expressed in the central nervous system and contribute to membrane hyperpolarization and regulation of neuronal excitability. Therapeutic strategies that modulate SKCa channels are being explored for vascular and neurological indications.

The review notes a lack of knowledge regarding the outcomes of sustained activation of SK3 channels, which is a critical safety and efficacy consideration for any long-term therapy that enhances SKCa activity.

References

Finally, SK3 channels are widely expressed, especially in the central nervous system, and the result of prolonged activation of this population of K+ channels is unknown.

— Integrating Endothelial-Derived Hyperpolarizing Signaling into a Multitarget Therapeutic Strategy for Microvascular Disease (2508.01618 - Madeddu et al., 3 Aug 2025) in Efforts to create pharmaceuticals targeting K+ channels