Sugar and spice and potassium channel modulation

The 18^th century English poet William Cowper asserted in his 1785 treatise, “The Task: Book 2. The Timepiece,” that:

Variety's the very spice of life,

That gives it all its flavor.

If Cowper's contention is accurate, then the family of membrane potassium channels is spicy and flavorful indeed. The genomes of organisms as wide-ranging as nematode worms, fruit flies and humans contain 70 or more genes encoding the pore-forming α subunits of different kinds of potassium channels.¹ Adding to this variety at the level of DNA is the fact that potassium channel α subunit mRNA is subject in some organisms to extensive alternative splicing; because potassium channels are functional tetramers, the protein products of the splice variants may combine in different ways to produce a large number of potassium channels with different functional properties.² To give just one example, the dSlo gene in Drosophila, which encodes the α subunit of a large conductance (BK) calcium- and voltage-activated potassium channel, can be processed into some 144 splice products,³ which could in principle combine to give rise to as many as 144⁴ (that is, almost 430,000,000) different tetrameric channels from just a single gene! In brief, the combinatorial possibilities are nothing short of staggering.

And if this were not sufficient, additional structural and phenotypic variety is conferred by the fact that most (if not all) ion channels do not consist of α subunits alone. It has been known since the early days of ion channel purification that the pore-forming α subunits are associated with so-called auxiliary subunits (often named β, γ and so on) that contribute importantly to channel assembly, membrane targeting and function.⁴ Finally, these various subunit combinations can be modulated by post-translational modifications, including phosphorylation⁵ and glycosylation,⁶ sometimes by enzymes that are intimately associated with the ion channel protein itself.⁵

In a paper published in this volume of Channels, Huang et al⁷ add to the story of ion channel structural and functional diversity by investigating the role of glycosylation of the β2 auxiliary subunit on the mouse BK channel, mSlo. While, as indicated above, it has been known for some time that β subunit glycosylation can influence channel functional properties, Huang et al take things a step further by asking what the structural basis for this modulation by glycosylation might be. To this end they systematically mutate each of the 3 asparagine (N) residues in the extracellular loop of the β2 subunit that reside within consensus sequences for N-linked glycosylation, and identify the glycosylation of N96 as critical for the interaction of β2 with the mSlo α subunit. An interesting and unusual feature of this paper is that the authors don't simply stop with the identification of the key modulatory glycosylation site, but they go on to carry out molecular dynamics modeling that predicts structural changes in the α subunit that are dependent on glycosylation of the β subunit. The conclusion from these modeling studies is that β2 subunit glycosylation promotes the association of the β2 subunits into a tetrameric structure that, in turn, stabilizes a particular alignment of the α/β2 complex. Such a “tightened” structure can account for the diverse functional consequences of β2 subunit glycosylation described by Huang et al, suggesting that the primary effect of glycosylation is in fact to stabilize channel subunit assembly and the modulatory changes are downstream from that.

What are we to make of the astonishing variety of potassium channel functional phenotypes conferred by the multiple mechanisms summarized here, including N-linked glycosylation? We don't really know, but we can speculate that the diversity of structural combinations and modulatory mechanisms permits neurons to respond with enormous flexibility to changing inputs from other neurons and the environment. In any event, whatever the reasons for the variety might be, it is abundantly evident that sugars are important players that contribute to ion channel functional diversity.

Disclosure of potential conflicts of interest

No potential conflicts of interest were disclosed.