Ion Channel Assembly

Ion channels are typically assembled from many subunits that form the pore-lining structure. The number of subunits that form ion channels varies from subfamily to subfamily. For example, four subunits of voltage-gated potassium channels assemble to form a single ion channel. Likewise, inward rectifier ion channels are tetramers. Most ligand-gated ion channels are pentamers, and gap junction ion channels are hexamers.

Ion channels that are members of the same subfamily can assemble with each other because they share molecular determinants that allow them to interact. For example, there are four subfamilies of voltage-gated potassium channels, Kv1-Kv4, related to Shaker. It is known that members of one Kv subfamily can coassemble together, but not with members of the other subfamilies. By carefully designing chimeras between the different Kv genes, the Jan group identified a stretch of amino acids in the N-terminal cytoplasmic domain before S1 that determines whether two Kv channels can interact with each other. This region, called the T1 domain, appears to form a structural domain that by itself can form a stable tetrameric structure. The T1 domain has been solved by X-ray crystallography. Analysis of the structure of the T1 domain from different Kv subfamilies shows that the interface between the T1 domain from each subfamily differs structurally. This suggests that members of different Kv subfamilies cannot coassem-ble because their T1 domains are incompatible.

Ion channels assembled from different subunits will exhibit different functional properties. Because ion channels can assemble from several genes of a given subfamily, the number of potential ion channels is expanded combinatorially. The reason for this potential diversity is unknown. One possibility is that the incorporation of certain subunits is used to regulate ion channel selectivity, gating, or biosynthesis. The inclusion of a subunit with certain sequence motifs has been shown to be able to target an ion channel to specific compartments within the cell or alter the stability of an ion channel on the plasma membrane.

In vivo, ion channels are often part of a complex with accessory proteins that can modify its functional properties or stability in much the same way that mixing subunits can do so. These other proteins are often referred to as b subunits, with the ion channel being the a subunit. b subunits can be soluble or integral membrane proteins. In some cases, the ion channel cannot be expressed in heterologous systems without its accessory subunits, suggesting that the b subunit is an essential part of the functional ion channel complex.

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