A K Channels Are Multisubunit Protein Complexes

Kv channels are multisubunit protein complexes. The main pore-forming complex consists of a tetramer of a sub-units. Often, Kv channels also have accessory subunits. For example, the Kv1 channels consist of four membrane-spanning and pore-forming a subunits and up to four cytoplas-mic ß subunits (Isacoff et al., 1990; Rhodes et al., 1997). In heterologous cells, Kv1 a and ß subunits have been shown to heteromultimerize promiscuously, resulting in channels with biophysically and pharmacologically distinct properties (Ruppersberg et al., 1990; Hopkins et al., 1994; Rettig et al., 1994; Shamotienko et al., 1997). For example, homotetrameric channels consisting of Kv1.1 or Kv1.2 encode channels that give rise to slow, noninactivating outward rectifiers (Fig. 1B). In contrast, channels consisting of only Kv1.4 a subunits encode a fast transient (A-type) channel. When these Kv1 a subunits are co-expressed, channels with

Figure I Voltage-dependent K+ (Kv) channels are localized at and near nodes of Ranvier. (A) The Kv channels make up a large family of homologous proteins (dendrogram created using ClustalW). Kv channel subunits are topologically similar with intracellular N- and C-termini, a positively charged transmembrane segment, and a K+ selective pore (P-loop). (B) Heteromultimerization of Kv1 channels results in channels with properties intermediate to those of homomultimeric channels. For example, addition of Kv1.4 into a channel containing Kvl.1 and/or Kv1.2 converts the channel from noninacti-vating to inactivating. (C) A rat optic nerve triple-labeled for Kv1.2 (blue), Caspr (red), and Nav channels (green), which label juxtaparanodes, paranodes, and nodes, respectively. (Reprinted with permission from Rasband and Shrager, 2000, copyright 2000 by the Journal of Physiology.) (D) Kv channels and their localization in myelinated nerve fibers.

Figure I Voltage-dependent K+ (Kv) channels are localized at and near nodes of Ranvier. (A) The Kv channels make up a large family of homologous proteins (dendrogram created using ClustalW). Kv channel subunits are topologically similar with intracellular N- and C-termini, a positively charged transmembrane segment, and a K+ selective pore (P-loop). (B) Heteromultimerization of Kv1 channels results in channels with properties intermediate to those of homomultimeric channels. For example, addition of Kv1.4 into a channel containing Kvl.1 and/or Kv1.2 converts the channel from noninacti-vating to inactivating. (C) A rat optic nerve triple-labeled for Kv1.2 (blue), Caspr (red), and Nav channels (green), which label juxtaparanodes, paranodes, and nodes, respectively. (Reprinted with permission from Rasband and Shrager, 2000, copyright 2000 by the Journal of Physiology.) (D) Kv channels and their localization in myelinated nerve fibers.

intermediate biophysical properties result (e.g., inclusion of a Kv1.4 a subunit can convert channels with Kv1.1 or Kv1.2 subunits to inactivating channels with transient currents (Ruppersberg et al., 1990; Fig. 1B).

Kv channel subunits also heteromultimerize in vivo to form K+ channels. This conclusion is based on a variety of data including co-immunoprecipitation, co-purification via column chromatography, and co-localization (Sheng et al., 1993; Wang et al., 1993; Rhodes et al., 1995). For example, Kv4.2 and Kv4.3 subunits have been shown to form functional heteromultimers in mammalian heart (Guo et al., 2002), whereas Kv3.1 and Kv3.2 form heteromultimeric channels in neurons of the globus pallidus (Hernandez-Pineda et al., 1999). Since Kv1a subunits are expressed widely throughout the nervous system (Monaghan et al., 2001), the heteromultimerization of subunits could, in principle, result in the expression of an enormous number of Kv channels with different properties. However, co-immuno-precipitation experiments have shown that only a relatively small number of subunit combinations can be detected (Rhodes et al., 1997; Shamotienko et al., 1997).

In addition to altering the biophysical properties of channels, recent experiments have shown that the kinds of Kv1 a subunits present in a channel can dramatically influence the surface expression of the channel, and that these properties are regulated by a retention signal localized to the channel pore (Manganas and Trimmer, 2000; Manganas et al., 2001; Zhu et al., 2001, 2003). Thus, excitable cells may modulate K+ currents through regulating the kinds of subunits expressed in a channel complex, which in turn regulates both the biophysical properties of the channels and their surface expression.

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