the schizophrenia-associated kv11.1-3.1 isoform results in reduced current accumulation during repetitive brief depolarizations的schizophrenia-associated kv11.1 - 3.1同种型结果在减少当前的积累在重复简单的去极化.pdfVIP

The Schizophrenia-Associated Kv11.1-3.1 Isoform Results in Reduced Current Accumulation during Repetitive Brief Depolarizations Juliane Heide1,2,3, Stefan A. Mann1,2, Jamie I. Vandenberg1,2,3* 1Victor Chang Cardiac Research Institute, Darlinghurst, NSW, Australia, 2 St. Vincent’s Clinical School, University of New South Wales, Darlinghurst, NSW, Australia, 3 Schizophrenia Research Institute, Darlinghurst, NSW, Australia Abstract Recent genome wide association studies identified a brain and primate specific isoform of a voltage-gated potassium channel, referred to as Kv11.1-3.1, which is significantly associated with schizophrenia. The 3.1 isoform replaces the first 102 amino acids of the most abundant isoform (referred to as Kv11.1-1A) with six unique amino acids. Here we show that the Kv11.1-3.1 isoform has faster rates of channel deactivation but a slowing of the rates of inactivation compared to the Kv11.1- 1A isoform. The Kv11.1-3.1 isoform also has a significant depolarizing shift in the voltage-dependence of steady-state inactivation. The consequence of the altered gating kinetics is that there is lower current accumulation for Kv11.1-3.1 expressing cells during repetitive action potential firing compared to Kv11.1-1A expressing cells, which in turn will result in longer lasting trains of action potentials. Increased expression of Kv11.1-3.1 channels in the brain of schizophrenia patients might therefore contribute to disorganized neuronal firing. Citation: Heide J, Mann SA, Vandenberg JI (2012) The Schizophrenia-Associated Kv11.1-3.1 Isoform Results in Reduced Current Accumulation during Repetitive Brief Depolarizations. PLoS ONE 7(9): e45624. doi:10.1371/journal.pone.0045624 Editor: Jon T. Brown, University of Bristol, United Kingdom Received May 29, 2012; Accepted August 20, 2012; Published September 24, 2012