Abstract
β subunits of mammalian sodium channels play important roles in modulating the expression and gating of mammalian sodium channels. However, there are no orthologs of β subunits in insects. Instead, an unrelated protein, TipE in Drosophila melanogaster and its orthologs in other insects, is thought to be a sodium channel auxiliary subunit. In addition, there are four TipE-homologous genes (TEH1-4) in D. melanogaster and three to four orthologs in other insect species. TipE and TEH1-3 have been shown to enhance the peak current of various insect sodium channels expressed in Xenopus oocytes. However, limited information is available on how these proteins modulate the gating of sodium channels, particularly sodium channel variants generated by alternative splicing and RNA editing. In this study, we compared the effects of TEH1 and TipE on the function of three Drosophila sodium channel splice variants, DmNav9-1, DmNav22, and DmNav26, in Xenopus oocytes. Both TipE and TEH1 enhanced the amplitude of sodium current and accelerated current decay of all three sodium channels tested. Strikingly, TEH1 caused hyperpolarizing shifts in the voltage-dependence of activation, fast inactivation and slow inactivation of all three variants. In contrast, TipE did not alter these gating properties except for a hyperpolarizing shift in the voltage-dependence of fast inactivation of DmNav26. Further analysis of the gating kinetics of DmNav9-1 revealed that TEH1 accelerated the entry of sodium channels into the fast inactivated state and slowed the recovery from both fast- and slow-inactivated states, thereby, enhancing both fast and slow inactivation. These results highlight the differential effects of TipE and TEH1 on the gating of insect sodium channels and suggest that TEH1 may play a broader role than TipE in regulating sodium channel function and neuronal excitability in vivo.
Highlights
Voltage-gated sodium channels are transmembrane proteins that are critical for the initiation and propagation of action potentials in neurons and other excitable cells [1]
To test whether changes in gating caused by TEH1 were responsible for the reduced channel sensitivity to deltamethrin, we examined the effect of the multiple depolarizing-prepulses on the stability of peak sodium current in channels coexpressed with TipE or TEH1
While the roles of mammalian sodium channel β subunits in modulating sodium channel activities have been extensively studied, research on auxiliary subunits of insect sodium channels is limited
Summary
Voltage-gated sodium channels are transmembrane proteins that are critical for the initiation and propagation of action potentials in neurons and other excitable cells [1]. Sodium channels open, resulting in sodium ion influx and further depolarization of the membrane potential. This process is called channel activation, which is responsible for the rapidly rising phase of action potentials. Sodium channels inactivate rapidly, within a few milliseconds in a process known as fast inactivation. In response to prolonged depolarization (seconds to minutes), sodium channels progressively enter into more stable, slow-inactivated states. This process is known as slow inactivation, which is important for regulating membrane excitability, action potential patterns and spike frequency adaptation [2]
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