Potassium channel structure: domain by domain

doi:10.1016/S0959-440X(00)00114-7

Current Opinion in Structural Biology

Volume 10, Issue 4, 1 August 2000, Pages 456-461

https://doi.org/10.1016/S0959-440X(00)00114-7 Get rights and content

Abstract

Since the determination of the structure of a bacterial potassium channel, the ion channel community has managed to gain momentum in the quest for a complete picture. The information is coming at a steady flow, on a domain by domain basis. Recent discoveries are starting to reveal clues to the complex manner in which potassium channels show enormous diversity of function and also to their methods of regulation. Currently, the structures of four domains are known, with the most recent addition being the Kvβ structure. As efforts continue in the study of the transmembrane domains, especially the voltage-sensing apparatus, there has been a new realization with respect to the identification and role of the cytoplasmic domains in protein–protein interactions in particular. An additional discovery, considerably aided by recent genomic analysis, is that potassium channels comprising subunits with two pore regions and four transmembrane helices combined in a dimeric fashion are abundant and are probable targets for local anesthetics.

Introduction

Eukaryotic potassium channels participate in a large number of cellular functions, from the regulation of cardiac electrical patterns to signal transduction pathways. In prokaryotes, regulation of the intracellular potassium level is crucial to cell survival. Indeed, sequencing studies predict that there are over one hundred unique potassium channel genes in the Caenorhabditis elegans genome. This diversity [1] is aided considerably by the manner in which the daedal hand of nature has designed the blueprints for potassium channel subunits (Figure 1). The sheer pace of potassium channel research makes it difficult to compile a comprehensive review that would not be out of date by the time of publication. Here, we discuss recent developments that, in our view, are likely to influence the direction of channel research.

Section snippets

Overall architecture of four classes

Potassium channels are composed of α subunits and β subunits. The subunit responsible for the actual conduction of potassium across the lipid bilayer is the integral membrane α subunit, the four main classes of which are shown in Figure 1. Specifically, the part responsible for potassium selectivity is a small stretch of amino acids referred to as the ‘P-region’ (P for pore-forming). Within this region is a highly conserved sequence, the signature sequence GY/FG, which defines potassium channel

N- and C-terminal cytoplasmic domains

Within each α-subunit class, there are various families based on sequence similarity. Within each family, heteromultimerization occurs, enabling nature to generate even more diversity. This heteromultimerization has been shown to be controlled in Kv channels by a region from the N-terminal section of the α subunit, located in the cytoplasm, called the T1 [5] or NAB domain [6]. The structure of the isolated T1 tetramer, first solved in 1998 in our laboratory [7^••], explains what governs

Kvβ subunits

In contrast to the large number of protein sequences identified for the α subunits of potassium channels, the number of sequences discovered for the β subunits is very small; so far, only three genes with various splice variants for the voltage-gated potassium channels [21]. The calcium-dependent potassium channel BK has a β subunit that differs from those of the Kv channels, being composed of two TM regions, with both termini intracellularly located.

The soluble β subunits have been shown to

Anesthetics and 4TM/2P channels

Volatile anesthetics have been proposed to act on the inhibitory ligand-gated ion channels, such as GABA and glycine receptors. These receptors cause an influx of chloride ions into the cell, thereby causing the membrane to hyperpolarize and inhibiting neuronal transmission. Membrane hyperpolarization can also occur as a result of the opposite effect, that is, cations flowing out of the cell. Recently, Patel et al. [29^•] have shown that certain mammalian potassium channels are activated by

Commonalities in architecture between prokaryotes and eukaryotes

MacKinnon et al. [31^•] demonstrated that the potassium channel α-subunit core region is highly conserved between eukaryotes and prokaryotes (by introducing a common toxin-binding interface), indicating that the topology of KcsA is preserved in higher organism potassium channels. This idea was given a further boost last year, when Gouaux and colleagues [32^••] identified a prokaryotic glutamate receptor. Before that, glutamate receptor sequences were only known for eukaryotes. The receptor,

Outlook

Structural biologists are starting to piece together the complex workings of potassium channels on a domain by domain basis. These structures are not only providing important answers concerning the biological importance of potassium channels, but are also starting to give new perspectives on the dynamics of the channel 35, 36, 37. For example, how does the channel open and close? How does the chemistry of the cell regulate the behavior of the channel? These questions will not be directly

Acknowledgements

We thank our colleagues for general discussions on potassium channels. SC is a recipient of a Klingenstein award in neuroscience and is funded by the National Institutes of Health. PCB is a Wellcome Trust Travelling Fellow. TR is funded by a National Defense Science and Engineering Graduate Fellowship from the United States Airforce.

References and recommended reading

Papers of particular interest, published within the annual period of review, have been highlighted as:

• of special interest
•• of outstanding interest

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ReviewPotassium channel structure: domain by domain

Abstract

Introduction

Section snippets

Overall architecture of four classes

N- and C-terminal cytoplasmic domains

Kvβ subunits

Anesthetics and 4TM/2P channels

Commonalities in architecture between prokaryotes and eukaryotes

Outlook

Acknowledgements

References and recommended reading

Neuron

Neuron

J Mol Biol

Biochem Biophys Res Commun

Curr Opin Neurobiol

Curr Opin Neurobiol

J Biol Chem

Neuron

Cell

Molecular diversity of K+ channels

Ann NY Acad Sci

The structure of the potassium channel: molecular basis of K+ conduction and selectivity

Science

Immunolocalization of the arachidonic acid and mechanosensitive baseline TRAAK potassium channel in the nervous system

Neuroscience

Genomic organization of nematode 4TM K+ channels

Ann NY Acad Sci

Assembly of voltage-gated potassium channels

J Biol Chem

Crystal structure of the tetramerization domain of the Shaker potassium channel

Nature

Crystal structure of the BTB domain from PLZF

Proc Natl Acad Sci USA

Structure of the VHL ElonginC-ElonginB complex: implications for VHL tumor suppressor function

Science

Crystal structure and functional analysis of the HERG potassium channel N-terminus: a eukaryotic PAS domain

Cell

Carboxy-terminal domain mediates assembly of the voltage-gated rat ether-a-go-go potassium channel

EMBO J

A recessive C-terminal Jervell and Lange-Nielsen mutation of the KCNQ1 channel impairs subunit assembly

EMBO J

Control of channel gating by protein phosphorylation: structural switches of the inactivation gate

Nat Struct Biol

Voltage-dependent activation of potassium channels is coupled to T1 domain structure

Nat Struct Biol

Association of Src tyrosine kinase with a human potassium channel mediated by SH3 domain

Science

Functional and molecular aspects of voltage-gated K+ channel β subunits

Ann NY Acad Sci

Review
Potassium channel structure: domain by domain

Molecular diversity of K⁺ channels

The structure of the potassium channel: molecular basis of K⁺ conduction and selectivity

Genomic organization of nematode 4TM K⁺ channels

Functional and molecular aspects of voltage-gated K⁺ channel β subunits