Modulation of voltage-gated K ⁺ channels by the sodium channel β1 subunit

Abstract

Voltage-gated sodium (Na V ) and potassium (K V ) channels are critical components of neuronal action potential generation and propagation. Here, we report that Na V β1 encoded by SCN1b, an integral subunit of Na V channels, coassembles with and modulates the biophysical properties of K V 1 and K V 7 channels, but not K V 3 channels, in an isoform-specific manner. Distinct domains of Na V β1 are involved in modulation of the different K V channels. Studies with channel chimeras demonstrate that Na V β1-mediated changes in activation kinetics and voltage dependence of activation require interaction of Na V β1 with the channel's voltage-sensing domain, whereas changes in inactivation and deactivation require interaction with the channel's pore domain. A molecular model based on docking studies shows Na V β1 lying in the crevice between the voltage-sensing and pore domains of K V channels, making significant contacts with the S1 and S5 segments. Cross-modulation of Na V and K V channels by Na V β1 may promote diversity and flexibility in the overall control of cellular excitability and signaling. voltage-gated sodium (Na V ) and potassium (K V ) channels mediate the depolarization phase (1) and repolarization phase (2, 3), respectively, of neuronal action potentials. Although intrinsic domains within the Na V α subunits underlie voltage-dependent gating properties and sodium-specific permeation, five Na V β subunits (β1, β1B, β2, β3, β4) assemble with and modulate inactivation kinetics and the voltage dependence of activation and inactivation of Na V α subunits (1, 4). In addition, these Na V β subunits function in cell adhesion and contribute to neuronal migration, pathfinding, and fasciculation (4-8). Given their ubiquitous roles and distribution in the CNS, Na V β subunits play a major role in fine-tuning of action potential generation, propagation, and frequency. Subtle changes to their function have resulted in a range of detrimental neurological diseases in humans such as genetic epilepsy with febrile seizures plus (GEFS+), Dravet syndrome (severe myoclonic epilepsy of infancy), temporal lobe epilepsy, febrile seizures, and decreased responsiveness to the anticonvulsant drugs carbamazepine and phenytoin (7-12).K V channels are important contributors to action potential repolarization. K V channels in mammals are encoded by 40 genes grouped into 12 subfamilies (K V 1-K V 12). Na V β1, which was previously thought to be specific for Na V channels, was recently shown to coassemble with and modulate the properties of the K V 4.x subfamily of channels (13-15). In the rodent heart, Na V β1 coprecipitates with K V 4.3, and in heterologous expression systems it increases the amplitude of the K V 4.3 current and speeds up activation (14, 15). In the rodent brain, Na V β1 coprecipitates with K V 4.2, and in heterologous expression systems it enhances surface expression of the channel and increases current amplitude (13). Genetic knockout of Na V β1 in mice prolongs action potential firing in pyramidal neurons through i...

The Role of Non-pore-Forming β Subunits in Physiology and Pathophysiology of Voltage-Gated Sodium Channels

“…Subsequent experiments by this group using siRNA to knock down Scn1b expression in neonatal rat ventricular cardiomyocytes resulted in reduced sodium current and transient outward potassium current, demonstrating that Scn1b modulates multiple channel types in vivo (Deschenes et al 2008). More recently, β1 has been shown to modulate potassium currents expressed by Kv1.1, Kv1.2, Kv1.3, Kv1.6, or Kv7.2 (but interestingly not Kv3.1) in oocytes (Nguyen et al 2012). Importantly, immunoprecipitation from mouse brain revealed that β1 subunits associate with Kv4.2 (Marionneau et al 2012).…”

Sodium Channel β Subunits: Emerging Targets in Channelopathies

“…As the biophysical properties of each α subunit differ, at least in vitro, this offers the potential to finely tailor excitability to specific organ, cellular, or subcellular requirements in a dynamic fashion via specific combinations of α and β subunits. Importantly, β subunits also interact with and functionally modulate some VGKCs, particularly the K v 4 channels and K v 1.1 (5–7). The association of β subunits, especially β1, with VGSCs and VGKCs provides a means for channel cross-talk during the AP.…”

“…These adhesive functions are critical to brain development and thus to excitability, including the processes of neurite outgrowth, axon pathfinding, fasciculation, and cell migration, and are postulated to play similar roles in heart and peripheral nerve (3; 4). In their roles as ion channel modulators, not only of VGSCs but also voltage-gated K + channels (VGKCs) (5–7), β subunits make important contributions to the regulation of neuronal firing. As substrates for sequential cleavage by β- (BACE) and γ-secretases, β subunits contribute to not only cell adhesion but also to the regulation of VGSC α subunit gene expression (8).…”

Modulation of Kv7 channels and excitability in the brain

“…Navβ1 was originally considered as a beta subunit unique to voltage-gated sodium channels (Nav) [61]. More recently the promiscuity of this auxiliary protein was uncovered, first in its modulation of Kv4 [62], and more recently Kv1 and Kv7 subfamilies [63] (Fig. 1D).…”

“…1D). Navβ1 slows Kv7.2 channel activation at depolarized potentials [63]. An interesting addition to accessory proteins of the Kv7.2 subunit is β -site amyloid precursor protein cleaving enzyme 1 (BACE1), which was originally identified to produce neurotoxic β -amyloid [64] and known to cleave Navβs and increases sodium currents [65].…”