title: Intercalated disc-associated protein, mXin-alpha, influences surface expression of ITO currents in ventricular myocytes.
abstract: Mouse Xin-alpha (mXin-alpha) encodes a Xin repeat-containing, actin-binding protein localized to the intercalated disc (ICD). Ablation of mXin-alpha progressively leads to disrupted ICD structure, cardiac hypertrophy and cardiomyopathy with conduction defects during adulthood. Such conduction defects could be due to ICD structural defects and/or cell electrophysiological property changes. Here, we showed that despite the normal ICD structure, juvenile mXina-null cardiomyocytes (from 3~4-week-old mice) exhibited a significant reduction in the transient outward K+ current (ITO), similar to adult mutant cells. Juvenile but not adult mutant cardiomyocytes also had a significant reduction in the delayed rectifier K+ current. In contrast, the mutant adult ventricular myocytes had a significant reduction in the inward rectifier K+ current (IK1) on hyperpolarization. These together could account for the prolongation of action potential duration (APD) and the ease of developing early afterdepolarization observed in juvenile mXin-alpha-null cells. Interestingly, juvenile mXin-alpha-null cardiomyocytes had a notable decrease in the amplitude of intracellular Ca2+ transient and no change in the L-type Ca2+ current, suggesting that the prolonged APD did not promote an increase in intracellular Ca2+ for cardiac hypertrophy. Juvenile mXin-alpha-null ventricles had reduced levels of membrane-associated Kv channel interacting protein 2, an auxiliary subunit of ITO, and filamin, an actin cross-linking protein. We further showed that mXin-alpha interacted with both proteins, providing a novel mechanism for ITO surface expression.
authors.affiliation: Institute of Physiology, National Defense Medical Center, Taipei, Taiwan, ROC.
authors.forename: Fu-Chi
authors.initials: FC
authors.lastname: Chan
authors.forename: Chiao-Pei
authors.initials: CP
authors.lastname: Cheng
authors.forename: Kuo-Ho
authors.initials: KH
authors.lastname: Wu
authors.forename: Yao-Chang
authors.initials: YC
authors.lastname: Chen
authors.forename: Chih-Hsiung
authors.initials: CH
authors.lastname: Hsu
authors.forename: Elisabeth A
authors.initials: EA
authors.lastname: Gustafson-Wagner
authors.forename: Jenny Li-Chun
authors.initials: JL
authors.lastname: Lin
authors.forename: Qinchuan
authors.initials: Q
authors.lastname: Wang
authors.forename: Jim Jung-Ching
authors.initials: JJ
authors.lastname: Lin
authors.forename: Cheng-I
authors.initials: CI
authors.lastname: Lin
mesh_terms: D000818:Animals; D001483:Base Sequence; D002478:Cells, Cultured; D017931:DNA Primers; D006352:Heart Ventricles / Q000166:cytology / Q000378:metabolism* / Q000648:ultrastructure; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D046529:Microscopy, Electron, Transmission; D009124:Muscle Proteins / Q000378:metabolism* / Q000502:physiology; D020133:Reverse Transcriptase Polymerase Chain Reaction; D020798:Two-Hybrid System Techniques
chemical_list: D017931:DNA Primers; D009124:Muscle Proteins