Channelopathy-causing mutations in the SA/SB and HA/HB helices of K2.3 and K3.1 channels alter their apparent Ca sensitivity.

Small- and intermediate-conductance Ca-activated potassium (K2.x and K3.1, also called SK and IK) channels are activated exclusively by a Ca-calmodulin gating mechanism. Wild-type K2.3 channels have a Ca EC value of ∼0.3 μM, while the apparent Ca sensitivity of wild-type K3.1 channels is ∼0.27 μM. Heterozygous genetic mutations of K2.3 channels have been associated with Zimmermann-Laband syndrome and idiopathic noncirrhotic portal hypertension, while K3.1 channel mutations were reported in hereditary xerocytosis patients. K2.3_S436C and K2.3_V450L channels with mutations in the SA/SB helices exhibited hypersensitivity to Ca. The corresponding mutations in K3.1 channels also elevated the apparent Ca sensitivity. K3.1_S314P, K3.1_A322V and K3.1_R352H channels with mutations in the HA/HB helices are hypersensitive to Ca, whereas K2.3 channels with the equivalent mutations are not. The different effects of the equivalent mutations in the HA/HB helices on the apparent Ca sensitivity of K2.3 and K3.1 channels may imply distinct modulation of the two channel subtypes by the HA/HB helices. AP14145 reduced the apparent Ca sensitivity of the hypersensitive mutant K2.3 channels, suggesting the potential therapeutic usefulness of negative gating modulators.