Transmembrane auxiliary subunits of voltage-dependent ion channels.

Auxiliary subunits of voltage-dependent ion channels can be subdivided into two classes. One class consists of the entirely cytoplasmic intracellular subunits, which have no transmembrane domains such as the b subunit of the voltage-dependent Ca channel and the b subunit of the voltage-dependent K channel. The other class of auxiliary subunits contains at least one transmembrane domain and an extracellular glycosylated region. This review will concentrate on the transmembrane auxiliary subunits. For mammalian systems, these proteins include the a2d and g subunits of the voltage-dependent Ca channel, the b1 and b2 subunits of the Na channel, and the b subunit of the maxi-K or large conductance Ca-activated K channel. Most traditional voltage-dependent K channels and Cl channels have not been shown to have transmembrane-containing associated proteins, although a family of membrane proteins including IsK,Cl (minK) may fit into this category. Recent genetic approaches using Drosophila and Caenorhabditis elegans have begun to identify evolutionarily related subunits as well as unique proteins that also profoundly alter ion channel properties and expression. The interest in identifying and studying these primarily extracellular proteins lies in the diverse and often unknown means by which they modify ion channel function and expression. Many are capable of altering pharmacological interactions or bind drugs directly while others are likely ligands for extracellular matrix proteins and cell-cell interactions. Some are highly negatively charged and may screen surface charges or influence ion concentration near the pore region of the ion channel. All are glycosylated to some extent suggesting a role for these proteins in plasma membrane targeting and/or subunit folding.