Regulation of N- and C-type inactivation of Kv1.4 by pH_o and K⁺: evidence for transmembrane communication

Abstract

Kv1.4 encodes a slowly recovering transient outward current ( I to), which inactivates by a fast N-type (intracellular ball and chain) mechanism but has slow recovery due to C-type inactivation. C-type inactivation of the NH2-terminal deletion mutant (fKv1.4ΔN) was inhibited by 98 mM extracellular K+concentration ([K+]o), whereas N-type was unaffected. In 98 mM [K+]o, removal of intracellular K+ concentration ([K+]i) speeded C-type inactivation but had no effect on N-type inactivation, suggesting that C-type inactivation is sensitive to K+ binding to intracellular sites. C-type inactivation is thought to involve closure of the extracellular pore mouth. However, a valine to alanine mutation on the intracellular side of S6 (V561A) of fKv1.4ΔN alters recovery and results in anomalous speeding of C-type inactivation with increasing [K+]o. Extracellular pH (pHo) modulated both N- and C-type inactivation through an S5-H5 linker histidine (H508) with acidosis speeding both N- and C-type inactivation. Mutation of an extracellular lysine to a tyrosine (K532Y) slowed C-type inactivation and inhibited the pH dependence of both N- and C-type inactivation. These results suggest that mutations, [K+], and pH modulate inactivation through membrane-spanning mechanisms involving S6.

Acid-sensitive TWIK and TASK Two-pore Domain Potassium Channels Change Ion Selectivity and Become Permeable to Sodium in Extracellular Acidification

“…Voltage-gated Kv2.1 channels change ion selectivity during C-type inactivation (37). Extracellular acidification enhances C-type inactivation in Kv1 channels (16,38,39). K2P channels are thought to have a C-type inactivation gate at the selectivity filter close to the extracellular side of the channels (40 -42).…”

“…Such a histidine is also conserved in voltagegated K ϩ channels (Kv1.1, Kv1.4, and Kv1.5) and inward rectifying K ϩ channels (Kir2.1) (13,14). External protons inhibit TREK-1 K ϩ channels by inducing closure of the outer pore gate (5), similar to the C-type inactivation of Kv1 channels that has been well studied under external acidification (15,16). In contrast, the pH o -sensing histidine in conventional acid-sensitive K2P channels, TASK-1 and TASK-3, along with TWIK-1 and TRESK-2 K ϩ channels, immediately follow the K ϩ channel selectivity sequence TXGYG of the P1-loop, whereas other K2P channels have an asparagine or methionine or tyrosine in the corresponding residue (see Fig.…”

Episodic ataxia type 1 mutation F184C alters Zn2+-induced modulation of the human K+ channel Kv1.4-Kv1.1/Kvβ1.1

“…Alternatively, they could change the overall structure of the nearby T1 domain, altering the predocking site for the inactivation particle before insertion into the inner vestibule (69). A similar mechanism has been suggested by Li and co-workers (34), who proposed that the EA1 mutation V408A, at an equivalent position of the Kv1.4 channel, modulates inactivation through membrane-spanning mechanisms involving S6 (34). Nevertheless, further studies are required to assess with certainty the molecular mechanisms underlying the altered biophysical properties of the channel caused by the mutation and by Zn 2ϩ .…”

The Effects of 4-Hydroxybenzoic Acid Identified from Bamboo (Dendrocalamus asper) Shoots on Kv1.4 Channel

“…Thus, the selectivity filter is emptied from K + binding and collapsed (49,50), initiating inactivation. According to Claydon et al (51) and Li et al (52), the selectivity filter is also affected by acidic solution (low pH). As the released of H + competed against the binding to the selectivity filter, it signaled lower K + concentration within the selectivity filter causing the filter to collapse and hence enhancing the inactivation mechanism.…”