Distinct domains of the voltage-gated K⁺ channel Kvβ1.3 β-subunit affect voltage-dependent gating

Abstract

The Kvβ1.3 subunit confers a voltage-dependent, partial inactivation (time constant = 5.76 ± 0.14 ms at +50 mV), an enhanced slow inactivation, a hyperpolarizing shift in the activation midpoint, and an increase in the deactivation time constant of the Kv1.5 delayed rectifier. Removal of the first 10 amino acids from Kvβ1.3 eliminated the effects on fast and slow inactivation but not the voltage shift in activation. Addition of the first 87 amino acids of Kvβ1.3 to the amino terminus of Kv1.5 reconstituted fast and slow inactivation without altering the midpoint of activation. Although an internal pore mutation that alters quinidine block (V512A) did not affect Kvβ1.3-mediated inactivation, a mutation of the external mouth of the pore (R485Y) increased the extent of fast inactivation while preventing the enhancement of slow inactivation. These data suggest that 1) Kvβ1.3-mediated effects involve at least two distinct domains of this β-subunit, 2) inactivation involves open channel block that is allosterically linked to the external pore, and 3) the Kvβ1.3-induced shift in the activation midpoint is functionally distinct from inactivation.

A Marriage of Convenience: β-Subunits and Voltage-dependent K+ Channels

“…The Kv ␤1.1-subunit modifies the rate of inactivation in delayed rectifier channels like Kv1.4, but the voltage dependence of this process remains unchanged (8,11 nels (11). Both Kv ␤1.1-and ⌲v␤1.2-subunits produce a leftward shift of the conductance-voltage curves of Kv1.5 channels and increase the rate of inactivation (13). In addition, Kv␤1.3 slows deactivation and modifies the Kv1.5 response to PKA activation.…”

Structural Basis for Competition between Drug Binding and Kvβ1.3 Accessory Subunit-Induced N-Type Inactivation of Kv1.5 Channels

“…Kv␤ subunits bind to the N terminus of Kv1 subunits and induce a comparatively rapid "N-type" inactivation Sewing et al, 1996). In addition, Kv␤1.2 (De Biasi et al, 1997) and Kv␤1.3 (Uebele et al, 1998) subunits slow the rate of Kv1.5 channel deactivation and cause a negative shift in the voltage dependence of activation and inactivation gating. Kv␤2 subunits bind to the C termini of Kv2.2 or Kv4.3 channels to increase their cell surface expression without obvious effects on gating properties (Fink et al, 1996;Yang et al, 2001).…”

Molecular Basis for a High-Potency Open-Channel Block of Kv1.5 Channel by the Endocannabinoid Anandamide

“…However, we identified two mutations (V505A and I508A) in the lower portion of the S6 domain that markedly reduced AEA block. Val505 and Ile508 are also key residues in interaction with Kv1.5 channel blockers AVE0118, S0100176, vernakalan (Decher et al, 2004(Decher et al, , 2006Eldstrom et al, 2007) and the Kv␤1.3 N terminus (Uebele et al, 1998;Gulbis et al, 1999). Furthermore, Ile508 constitutes an important residue of the binding site for drugs ICAGEN-4, MSD-D, and S9947 (Strutz-Seebohm et al, 2007).…”