Calcium-activated potassium channels modulate calcium signaling cascades and membrane potential in both excitable and non-excitable cells. In this article we will review the physiological properties, the structure activity relationships of the existing
peptide and small molecule modulators and the therapeutic importance of the three small-conductance channels KCa2.1-KCa2.3 (a.k.a. SK1-SK3) and the intermediate-conductance channel KCa3.1 (a.k.a. IKCa1). The
apamin-sensitive KCa2 channels contribute to the medium afterhyperpolarization and are crucial regulators of neuronal excitability. Based on behavioral studies with
apamin and on observations made in several transgenic mouse models, KCa2 channels have been proposed as targets for the treatment of
ataxia,
epilepsy,
memory disorders and possibly
schizophrenia and
Parkinson's disease. In contrast, KCa3.1 channels are found in lymphocytes, erythrocytes, fibroblasts, proliferating vascular smooth muscle cells, vascular endothelium and intestinal and airway epithelia and are therefore regarded as targets for various diseases involving these tissues. Since two classes of potent and selective small molecule KCa3.1 blocker, triarylmethanes and
cyclohexadienes, have been identified, several of these postulates have already been validated in animal models. The triarylmethane
ICA-17043 is currently in phase III clinical trials for
sickle cell anemia while another triarylmethane,
TRAM-34, has been shown to prevent vascular restenosis in rats and
experimental autoimmune encephalomyelitis in mice. Experiments showing that a
cyclohexadiene KCa3.1 blocker reduces
infarct volume in a rat
subdural hematoma model further suggest KCa3.1 as a target for the treatment of traumatic and possibly ischemic
brain injury. Taken together KCa2 and KCa3.1 channels constitute attractive new targets for several diseases that currently have no effective
therapies.