ReviewPotassium channel structure: domain by domain
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 The sheer pace of potassium channel research makes it difficult to compile a comprehensive review that would not be out of date by the time of publication.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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