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. 2012;7(9):e45624.
doi: 10.1371/journal.pone.0045624. Epub 2012 Sep 24.

The schizophrenia-associated Kv11.1-3.1 isoform results in reduced current accumulation during repetitive brief depolarizations

Juliane Heide  1 , Stefan A Mann, Jamie I Vandenberg
Affiliations

The schizophrenia-associated Kv11.1-3.1 isoform results in reduced current accumulation during repetitive brief depolarizations

Juliane Heide et al. PLoS One. 2012.

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.

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Conflict of interest statement

Competing Interests: The authors have declared that no competing interests exist.

Figures

Figure 1
Figure 1. Rates of activation for Kv11.1 channels at 0 mV.
A. Typical examples of Kv11.1-3.1 currents recorded at 37°C during an envelope-of-tails voltage clamp protocol to measure rates of activation at 0 mV. The voltage protocol is shown at the top of the panel. The dashed line highlights the peak tail current for each current trace. B. Normalized peak tail current plotted against duration of the test pulse for Kv11.1-1A (○) and Kv11.1-3.1 (•). The inset shows the mean ± SEM for time constants of activation (n = 4−5). τact, 0 mV for Kv11.1-1A (58±5 ms, n = 5) was not significantly larger than that for Kv11.1-3.1 (57±5 ms, n = 4).
Figure 2
Figure 2. Voltage dependence of steady-state activation for Kv11.1-1A and Kv11.1-3.1.
A. Typical families of current traces recorded at 37°C from Kv11.1-1A (left) and Kv11.1-3.1 (right) showing the last 100–150 ms of the activating step and 500 ms of the tail current recorded at −60 mV. Arrow indicates position where peak tail current was recorded. Inset at top of panel shows voltage protocol used to measure steady-state activation. B. Normalized peak tail currents plotted against voltages of the preceding test pulse for Kv11.1-1A (○) and Kv11.1-3.1 (•). Solid lines are fits of the Boltzmann function (see Eq. 1) giving V0.5 for steady-state activation of −31.4±1 mV for Kv11.1-1A and −35±1 mV for Kv11.1-3.1 (P<0.05).
Figure 3
Figure 3. Rates of deactivation for Kv11.1-1Aand Kv11.1-3.1A.
A. Typical currents recorded at 37°C during a protocol to measure rates of deactivation (voltage protocol show at top of panel, dashed box indicates the part of the voltage protocol for which current traces are shown) for Kv11.1-1A (left) and Kv11.1-3.1 (right). B. Magnification of the first 100 ms of the −120 mV tail current for Kv11.1-1A (grey) and Kv11.1-3.1 (black) show the characteristic hooked appearance reflecting recovery from inactivation followed by deactivation. C. Summary of τdeact (mean ± SEM) over the voltage range of −130 mV to −60 mV for Kv11.1-1A (○) and Kv11.1-3.1 (•). ***: p<0.001.
Figure 4
Figure 4. Inactivation properties of Kv11.1-1A and Kv11.1-3.1.
A. Typical family of Kv11.1-1A (left) and Kv11.1-3.1 (right) current traces recorded at 37°C during a protocol to measure rates of inactivation (voltage protocol shown at top of panel A, dashed box highlights the part of the traces shown). B. Magnification of the first 8 ms of the +60 mV step for Kv11.1-1A (grey) and Kv11.1-3.1 (black) indicating slower inactivation for Kv11.1-3.1 compared to Kv11.1-1A. C. Summary of rates of recovery from inactivation for Kv11.1-1A (□) and Kv11.1-3.1 (▪) (τrecov, measured from protocol shown in Fig. 3) over the voltage range −130 mV to −40 mV and rates of inactivation (τinact) for Kv11.1-1A (○) and Kv11.1-3.1 (•) over the voltage range −30 mV to +60 mV. Solid lines are the best fits of equation 2 to the data (see materials and methods). D. Midpoint of stead-state inactivation for Kv11.1-1A (○) and Kv11.1-3.1 (•) measured as the voltage at which τinact = τrecov (see methods for details). ***: p<0.001.
Figure 5
Figure 5. Action potential simulation for Kv11.1-A and Kv11.1-3.1.
Typical current responses for the 1st, 5th and 61st pulse for A. Kv11.1-1A and B. Kv11.1-3.1 during a pulse protocol where cells were repetitively depolarized to +40 mV for 5 ms, from a holding potential of −70 mV with interpulse interval of 15 ms (voltage protocol shown at top of panel). Currents were measured at 1 ms (red dashed line) and 3 ms (blue dashed line) and the values normalized to the peak tail current recorded for each cell at −120 mV after a 1 s step to +40 mV to fully activate the channels (data not shown). C. Normalized currents measured at 1 ms (red symbols) plotted against time for Kv11.1-1A (○), Kv11.1-1A/Kv11.1-3.1 (*) and Kv11.1-3.1 (•) with the 1st, 5th and 61st pulse highlighted by the black arrows. D. Normalized currents measured at 3 ms (blue symbols) plotted against time for Kv11.1-1A (○) and Kv11.1-3.1 (•). 1st, 5th and 61th pulse highlighted with black arrows. The data for the Kv11.1-1A/Kv11.1-3.1 channels has been left out of panel D for purposes of clarity (due to overlapping error bars). Panel C and D only show every second data point for purposes of clarity.
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