Channelopathy-causing mutations in the S₄₅A/S₄₅B and HA/HB helices of K_Ca2.3 and K_Ca3.1 channels alter their apparent Ca²⁺ sensitivity

Small- and intermediate-conductance Ca²⁺-activated potassium (K_Ca2.x and K_Ca3.1, also called SK and IK) channels are activated exclusively by a Ca²⁺-calmodulin gating mechanism. Wild-type K_Ca2.3 channels have a Ca²⁺ EC₅₀ value of ∼0.3 μM, while the apparent Ca²⁺ sensitivity of wild-type K_Ca3.1 channels is ∼0.27 μM. Heterozygous genetic mutations of K_Ca2.3 channels have been associated with Zimmermann-Laband syndrome and idiopathic noncirrhotic portal hypertension, while K_Ca3.1 channel mutations were reported in hereditary xerocytosis patients. K_Ca2.3_S436C and K_Ca2.3_V450L channels with mutations in the S₄₅A/S₄₅B helices exhibited hypersensitivity to Ca²⁺. The corresponding mutations in K_Ca3.1 channels also elevated the apparent Ca²⁺ sensitivity. K_Ca3.1_S314P, K_Ca3.1_A322V and K_Ca3.1_R352H channels with mutations in the HA/HB helices are hypersensitive to Ca²⁺, whereas K_Ca2.3 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 K_Ca2.3 and K_Ca3.1 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 K_Ca2.3 channels, suggesting the potential therapeutic usefulness of negative gating modulators.