A590T mutation in KCNQ1 C-terminal helix D decreases I_Ks channel trafficking and function but not Yotiao interaction

KCNQ1 encodes the α subunit of the voltage-gated channel that mediates the cardiac slow delayed rectifier K⁺ current (I_Ks). Here, we report a KCNQ1 allele encoding an A590T mutation [KCNQ1(A590T)] found in a 39-year-old female with a mild QT prolongation. A590 is located in the C-terminal α helical region of KCNQ1 that mediates subunit tetramerization, membrane trafficking, and interaction with Yotiao. This interaction is known to be required for the proper modulation of I_Ks by cAMP. Since previous studies reported that mutations in the vicinity of A590 impair I_Ks channel surface expression and function, we examined whether and how the A590T mutation affects the I_Ks channel. Electrophysiological measurements in HEK-293T cells showed that the A590T mutation caused a reduction in I_Ks density and a right-shift of the current-voltage relation of channel activation. Immunocytochemical and immunoblot analyses showed the reduced cell surface expression of KCNQ1(A590T) subunit and its rescue by coexpression of the wild-type KCNQ1 [KCNQ1(WT)] subunit. Moreover, KCNQ1(A590T) subunit interacted with Yotiao and had a cAMP-responsiveness comparable to that of KCNQ1(WT) subunit. These findings indicate that the A590 of KCNQ1 subunit plays important roles in the maintenance of channel surface expression and function via a novel mechanism independent of interaction with Yotiao.