Small- and intermediate-conductance Ca2+-activated potassium (KCa2.x and KCa3.1, also called SK and IK)
channels are activated exclusively by a Ca2+-calmodulin gating mechanism. Wild-type KCa2.3 channels have a
Ca2+ EC50 value of ~0.3 μM, while the apparent Ca2+ sensitivity of wild-type KCa3.1 channels is ~0.27 μM.
Heterozygous genetic mutations of KCa2.3 channels have been associated with Zimmermann-Laband syndrome
and idiopathic noncirrhotic portal hypertension, while KCa3.1 channel mutations were reported in hereditary
xerocytosis patients. KCa2.3_S436C and KCa2.3_V450L channels with mutations in the S45A/S45B helices exhibited
hypersensitivity to Ca2+. The corresponding mutations in KCa3.1 channels ... More
Small- and intermediate-conductance Ca2+-activated potassium (KCa2.x and KCa3.1, also called SK and IK)
channels are activated exclusively by a Ca2+-calmodulin gating mechanism. Wild-type KCa2.3 channels have a
Ca2+ EC50 value of ~0.3 μM, while the apparent Ca2+ sensitivity of wild-type KCa3.1 channels is ~0.27 μM.
Heterozygous genetic mutations of KCa2.3 channels have been associated with Zimmermann-Laband syndrome
and idiopathic noncirrhotic portal hypertension, while KCa3.1 channel mutations were reported in hereditary
xerocytosis patients. KCa2.3_S436C and KCa2.3_V450L channels with mutations in the S45A/S45B helices exhibited
hypersensitivity to Ca2+. The corresponding mutations in KCa3.1 channels also elevated the apparent Ca2+
sensitivity. KCa3.1_S314P, KCa3.1_A322V and KCa3.1_R352H channels with mutations in the HA/HB helices are
hypersensitive to Ca2+, whereas KCa2.3 channels with the equivalent mutations are not. The different effects of
the equivalent mutations in the HA/HB helices on the apparent Ca2+ sensitivity of KCa2.3 and KCa3.1 channels
may imply distinct modulation of the two channel subtypes by the HA/HB helices. AP14145 reduced the
apparent Ca2+ sensitivity of the hypersensitive mutant KCa2.3 channels, suggesting the potential therapeutic
usefulness of negative gating modulators.
