New Structures and Gating of Voltage-Dependent Potassium (Kv) Channels and Their Relatives: A Multi-Domain and Dynamic Question

Abstract

Voltage-dependent potassium channels (Kv channels) are crucial regulators of cell excitability that participate in a range of physiological and pathophysiological processes. These channels are molecular machines that display a mechanism (known as gating) for opening and closing a gate located in a pore domain (PD). In Kv channels, this mechanism is triggered and controlled by changes in the magnitude of the transmembrane voltage sensed by a voltage-sensing domain (VSD). In this review, we consider several aspects of the VSD–PD coupling in Kv channels, and in some relatives, that share a common general structure characterized by a single square-shaped ion conduction pore in the center, surrounded by four VSDs located at the periphery. We compile some recent advances in the knowledge of their architecture, based in cryo-electron microscopy (cryo-EM) data for high-resolution determination of their structure, plus some new functional data obtained with channel variants in which the covalent continuity between the VSD and PD modules has been interrupted. These advances and new data bring about some reconsiderations about the use of exclusively a classical electromechanical lever model of VSD–PD coupling by some Kv channels, and open a view of the Kv-type channels as allosteric machines in which gating may be dynamically influenced by some long-range interactional/allosteric mechanisms.

Voltage-dependent activation in EAG channels follows a ligand-receptor rather than a mechanical-lever mechanism

“…The similar structures of hERG and K V 10.1 (12,13) showing a nonswapped arrangement of the pore and voltage sensor domains suggest that voltage-gating of these channels does not follow the classical mechanical-lever model in which S4-S5 L constricts the S6 T gate (21). Also, functional evidence obtained by several groups including ours, strongly suggests that hERG channels do not follow the mechanical-lever model (14,15).…”

The EAG Voltage-Dependent K+ Channel Subfamily: Similarities and Differences in Structural Organization and Gating

“…The three-dimensional protein structures of many ion channels, including some EAG subfamily channels and other members of the structurally-related CNBD family have been elucidated, initially using X-ray crystallography and NMR spectroscopy, and currently, by the spectacular improvements in single particle cryo-EM (reviewed in Vandenberg et al, 2017;Lau et al, 2018;James and Zagotta, 2018;Okamura and Okochi, 2019;Barros et al, 2019). The discovery that, despite their shared common primary organization, the EAG channels and other members of the Kv family can adopt two main architectural patterns in their transmembrane core (Figure 3), caused an essential breakthrough in our view of the structural basis of the molecular mechanism(s) involved in the voltage-triggered gating of these entities.…”

“…Interestingly, some of the cytoplasmic EAG channels sections display a high degree of homology with other domains from channels outside the Kv family [e.g., the cyclic nucleotide-gated (CNG), the hyperpolarization-activated and cyclic nucleotide-gated (HCN) and some inwardly rectifying plant K + channels], all of them pertaining to the named "S4" or "6TM1P" group of the pore-loop channel family, but having different selectivity, or no or even inverted voltage dependence Yu et al, 2005;Ashcroft, 2006;Lau et al, 2018). Indeed, the presence of intracellular domains either able to bind cyclic nucleotides (cyclic nucleotide-binding domain, CNBD), or sharing high structural homologies with those domains but unable to bind nucleotides (cyclic nucleotide-binding homology domain, CNBHD), has allowed classifying the EAG, CNG, and HCN channels under the named CNBD channel family , even though the voltage-dependence, selectivity, and cyclic nucleotide regulation of the EAG channels are different from those of the CNG and HCN channels Barros et al, 2019).…”

Challenges Faced with Small Molecular Modulators of Potassium Current Channel Isoform Kv1.5

“…To date, various kinds of Kv1.5 modulators have been disclosed, herein, we summarize the molecular structures and functionality of different types of Kv1.5 modulators with their chemical structure as follows (Table 1, Figure 2). As shown in Table 1, the existing Kv1.5 modulators can be divided into four categories: clinical cardiovascular drugs (1)(2)(3)(4)(5)(6)(7)(8)(9)(10)(11)(12)(13)(14), other clinical drugs (15)(16)(17)(18)(19)(20)(21)(22)(23)(24)(25)(26)(27)(28), drugs in development (29)(30)(31)(32)(33)(34)(35)(36)(37), and natural products (38)(39)(40)(41)(42)(43)(44)(45)(4...…”

“…The major voltage-gated K + channels expressed in the vasculature are Kv1.2, Kv1.5, Kv2.1, and Kv7.4/7.5 [21]. Kv1.3, another Shaker-related family voltage-gated K + channel, is closely related to the hERG channels regulated by Kv1.1 [22], which are the important targets influencing the prolongation of Q band to the end of T band (QT) syndrome and torsade pointes attributed to the gain-of-function mutations of clinical candidates whose details are being requested by drug regulatory authorities. Limitations in the ability of high-throughput screening methods to monitor the complex behavior of hERG have restricted the discovery of activators.…”