Mechanistic basis for paradoxical antiproliferative effects of KCa3.1 modulators

Determine the cellular and molecular mechanisms by which both activators (e.g., SKA-31 and related positive modulators) and inhibitors of the intermediate-conductance calcium-activated potassium channel KCa3.1 (KCNN4) similarly suppress proliferation of vascular smooth muscle cells, despite exerting opposite modulatory actions on channel activity.

Background

The review discusses pharmacological strategies targeting endothelial and smooth muscle K+ channels to enhance hyperpolarization-mediated vasodilation and address microvascular disease. KCa3.1 channels influence vascular smooth muscle phenotypic switching and proliferation, making them attractive therapeutic targets in atherosclerosis and restenosis.

Unexpectedly, both KCa3.1 activators (such as SKA-31) and KCa3.1 inhibitors have been reported to reduce smooth muscle cell proliferation, posing a mechanistic paradox that complicates drug development and safety assessment. Clarifying the underlying pathways is crucial for rational therapeutic design.