Channelopathy-causing mutations in the S < sub > 45 < /sub > A/S < sub > 45 < /sub > B and HA/HB helices of K < sub > Ca < /sub > 2.3 and K < sub > Ca < /sub > 3.1 channels alter their apparent Ca < sup > 2+ < /sup > sensitivity

Cell Calcium. 2022 Jan 8;102:102538. doi: 10.1016/j.ceca.2022.102538. Online ahead of print.ABSTRACTSmall- 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.PMID:35030515 | DOI:10.1016/j.ceca.2022.102538
Source: Cell Calcium - Category: Cytology Authors: Source Type: research