Endothelial small-conductance and intermediate-conductance KCa channels: an update on their pharmacology and usefulness as cardiovascular targets

Abstract

Most cardiovascular researchers are familiar with intermediate-conductance KCa3.1 and small-conductance KCa2.3 channels because of their contribution to endothelium-derived hyperpolarization. However, to immunologists and neuroscientists, these channels are primarily known for their role in lymphocyte activation and neuronal excitability. KCa3.1 is involved in the proliferation and migration of T cells, B cells, mast cells, macrophages, fibroblasts, and dedifferentiated vascular smooth muscle cells and is, therefore, being pursued as a potential target for use in asthma, immunosuppression, and fibroproliferative disorders. In contrast, the 3 KCa2 channels (KCa2.1, KCa2.2, and KCa2.3) contribute to the neuronal medium afterhyperpolarization and, depending on the type of neuron, are involved in determining firing rates and frequencies or in regulating bursting. KCa2 activators are accordingly being studied as potential therapeutics for ataxia and epilepsy, whereas KCa2 channel inhibitors like apamin have long been known to improve learning and memory in rodents. Given this background, we review the recent discoveries of novel KCa3.1 and KCa2.3 modulators and critically assess the potential of KCa activators for the treatment of diabetes and cardiovascular diseases by improving endothelium-derived hyperpolarizations.

FIGURE 1

Cartoon of the physiological role of KCa3.1. The channel is activated by increases in intracellular Ca²⁺ following Ca²⁺ release from the ER (endoplasmatic reticulum), and/or Ca²⁺ influx through inward-rectifier Ca²⁺ channels like CRAC (Ca²⁺ release activated Ca²⁺ channel) or TRP (transient receptor potential) channels. PLC; phospholipase C; IP₃ inositol-triphosphate; CAM; calmodulin.

FIGURE 2

Cartoon depicting the different Ca²⁺ sources involved in KCa2 channel activation. In neurons KCa2 channels are often localized in close proximity to NMDA receptors or to voltage-gated Ca²⁺ channels (Cav), which can induce Ca²⁺-induced Ca²⁺ release from ryanodine receptors (RyR). KCa2 channels can further be activated through G-protein induced Ca²⁺-release from inositol-triphosphate (IP₃) receptors and/or Ca²⁺ influx through TRP (transient receptor potential) channels.

FIGURE 3

Structures and potencies of commonly used or recently developed KCa3.1 and KCa2 modulators.