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

Francisco Barros,Pedro Domínguez,Pilar De La Peña,Luisa Sierra,Luis Pardo

doi:10.3390/ijms20020248

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.

Highlights

Ion channels are macromolecular pores that permit the passive flow of ions across the membrane down their electrochemical gradients
We will analyze several aspects of the voltage-sensing domain (VSD)–PD coupling, according to recent advances in the knowledge of channel architecture in several members of the six-transmembrane domain one-pore domain subfamily (6TM1P) to which the Kv channels belong, and to 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 necessary reconsideration regarding the sufficiency of a classical electromechanical lever-based mechanism alone to explain VSD–PD coupling in some Kv channels, opening a view of the Kv-type channels as allosteric machines, in the sense that gating may be dynamically influenced by conformational changes that can be distant from the actual gate

Summary

Introduction

Ion channels are macromolecular (mostly gated) pores that permit the passive flow of ions across the membrane down their electrochemical gradients. We will analyze several aspects of the VSD–PD coupling, according to recent advances in the knowledge of channel architecture in several members of the six-transmembrane domain one-pore domain subfamily (6TM1P) to which the Kv channels belong, and to 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 necessary reconsideration regarding the sufficiency of a classical electromechanical lever-based mechanism alone to explain VSD–PD coupling in some Kv channels, opening a view of the Kv-type channels as allosteric machines, in the sense that gating may be dynamically influenced by conformational changes that can be distant from the actual gate. Only mechanisms of primary channel opening and closing (activation and deactivation gating) will be considered here

Cryo-EM: A New Catalog of Kv and Other Ion Channel Structures

Swapped or Non-Swapped Organization of the Kv Structures?

Non-Domain-Swapped Kv Channel Relatives

Concluding Remarks