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. 2014 Jan 16:4:3721.
doi: 10.1038/srep03721.

PKA phosphorylation reshapes the pharmacological kinetics of BmK AS, a unique site-4 sodium channel-specific modulator

Z R Liu  1 , H Zhang  2 , J Q Wu  2 , J J Zhou  2 , Y H Ji  3
Affiliations

PKA phosphorylation reshapes the pharmacological kinetics of BmK AS, a unique site-4 sodium channel-specific modulator

Z R Liu et al. Sci Rep. .

Abstract

Although modulation of the activity of voltage-gated sodium channels (VGSCs) by protein kinase A (PKA) phosphorylation has been investigated in multiple preparations, the pharmacological sensitivity of VGSCs to scorpion toxins after PKA phosphorylation has rarely been approached. In this study, the effects of BmK AS, a sodium channel-specific modulator from Chinese scorpion Buthus martensi Karsch, on the voltage-dependent activation and inactivation of Nav1.2 were examined before and after PKA activation. After PKA phosphorylation, the pattern of dose-dependent modulation of BmK AS, on both Nav1.2α and Nav1.2 (α + β1) was reshaped. Meanwhile, the shifts in voltage-dependency of activation and inactivation induced by BmK AS were attenuated. The results suggested that PKA might play a role in different patterns how β-like toxins such as BmK AS modulate gating properties and peak currents of VGSCs.

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Conflict of interest statement

The authors declare no competing financial interests.

Figures

Figure 1
Figure 1. Time course of peak sodium current amplitude during PKA activation.
Peak sodium current amplitudes recorded from control (Open square), pre-administration of Iso (Open circle) and pre-administration of 500 nM BmK AS (Open triangle) are shown during 50-min time course.
Figure 2
Figure 2. BmK AS modulation of the sodium channel before and after PKA activation.
(A–C), Representative sodium current traces after treatment of 1 nM,10 nM or 100 nM BmK AS (Black). (D). 3-D diagram illustrates the inhibition rate of BmK AS on Nav1.2α before and after PKA activation.
Figure 3
Figure 3. Voltage dependence of activation and inactivation for Nav1.2 sodium channels.
The voltage-dependence of activation and inactivation are shown for α subunits alone (Left pannel) and (α + β1) subunits (Right pannel).
Figure 4
Figure 4. Kinetics for voltaged dependent activation and inactivation for Nav1.2 sodium channels.
Figure 5
Figure 5. Modulation of BmK AS on the inactivation kinetics of phosphorylated/non-phophorylated Nav1.2.
(A–C) Inactivation time constants and fraction of fast component modulated by BmK AS of each concentration (1, 10 and 100 nM).
Figure 6
Figure 6. The fractions of residual sodium current after depolarization to −20 mV for 10 ms in Xenopus oocytes, before (A) and after PKA phosphorylation (B)*P < 0.05; indicating significant difference between the control (white bar) and BmK AS (Dark bar) values.
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