hSK4/hIK1, a calmodulin-binding K-Ca channel in human T lymphocytes - Roles in proliferation and volume regulation

Human T lymphocytes express a Ca2+-activated K+ current (IK), whose roles a nd regulation are poorly understood. We amplified hSK4 cDNA hom human T lym phoblasts, and we showed that its biophysical and pharmacological propertie s when stably expressed in Chinese hamster ovary cells were essentially ide ntical to the native IK current. In activated lymphoblasts, hSK4 mRNA incre ased 14.6-fold (Kv1.3 mRNA increased 1.3-fold), with functional consequence s. Proliferation was inhibited when Kv1.3 and IK were blocked in naive T ce lls, but IK block alone inhibited re-stimulated lymphoblasts. IK and Kv1.3 were involved in volume regulation, but IK was more important, particularly in lymphoblasts. hSK4 lacks known Ca2+-binding sites; however, we mapped a Ca2+-dependent calmodulin (CaM)-binding site to the proximal C terminus (C t1) of hSK4. Full-length hSK4 produced a highly negative membrane potential (V-m) in Chinese hamster ovary cells, whereas the channels did not functio n when either Ctl or the distal C terminus was deleted (V-m similar to 0 mV ). Native IK (but not expressed hSK4) current was inhibited by CaM and CaM kinase antagonists at physiological V-m values, suggesting modulation by an accessory molecule in native cells. Our results provide evidence for incre ased roles for IK/hSK4 in activated T cell functions; thus hSK4 may be a pr omising therapeutic target for disorders involving the secondary immune res ponse.