K+ channel principal subunits are by far the largest and most diverse of the ion channels. This diversity originates partly from the large number of genes coding for K+ channel principal subunits, but also from other processes such as alternative splicing, generating multiple mRNA transcripts from a single gene, heteromeric assembly of different principal subunits, as well as possible RNA editing and posttranslational modifications. In this chapter, we attempt to give an overview (mostly in tabular format) of the different genes coding for K+ channel principal and accessory subunits and their genealogical relationships. We discuss the possible correlation of different principal subunits with native K+ channels, the biophysical and pharmacological properties of channels formed when principal subunits are expressed in heterologous expression systems, and their patterns of tissue expression. In addition, we devote a section to describing how diversity of K+ channels can be conferred by heteromultimer formation, accessory subunits, alternative splicing, RNA editing and posttranslational modifications. We trust that this collection of facts will be of use to those attempting to compare the properties of new subunits to the properties of others already known or to those interested in a comparison between native channels and cloned candidates.

A new member of a family of proteins characterized by structural similarity to dipeptidyl peptidase (DPP) IV known as DPP10 was recently identified and linked to asthma susceptibility; however, the cellular functions of DPP10 are thus far unknown. DPP10 is highly homologous to subfamily member DPPX, which we previously reported as a modulator of Kv4-mediated A-type potassium channels (Nadal, M. S., Ozaita, A., Amarillo, Y., Vega-Saenz de Miera, E., Ma, Y., Mo, W., Goldberg, E. M., Misumi, Y., Ikehara, Y., Neubert, T. A., and Rudy, B. (2003) Neuron. 37, 449 -461). We studied the ability of DPP10 protein to modulate the properties of Kv4.2 channels in heterologous expression systems. We found DPP10 activity to be nearly identical to DPPX activity and significantly different from DPPIV activity. DPPX and DPP10 facilitated Kv4.2 protein trafficking to the cell membrane, increased A-type current magnitude, and modified the voltage dependence and kinetic properties of the current such that they resembled the properties of A-type currents recorded in neurons in the central nervous system. Using in situ hybridization, we found DPP10 to be prominently expressed in brain neuronal populations that also express Kv4 subunits. Furthermore, DPP10 was detected in immunoprecipitated Kv4.2 channel complexes from rat brain membranes, confirming the association of DPP10 proteins with native Kv4.2 channels. These experiments suggest that DPP10 contributes to the molecular composition of A-type currents in the central nervous system. To dissect the structural determinants of these integral accessory proteins, we constructed chimeras of DPPX, DPP10, and DPPIV lacking the extracellular domain. Chimeras of DPPX and DPP10, but not DPPIV, were able to modulate the properties of Kv4.2 channels, highlighting the importance of the intracellular and transmembrane domains in this activity.We recently identified DPP10, a new member of a family of proteins characterized by structural similarity to dipeptidyl peptidase (DPP) 1 IV (1). DPPIV (also known as CD26) is a multifunctional protein. It is a membrane-bound enzyme belonging to the S9B prolyl oligopeptidase class of serine proteases. Its exopeptidase activity has great physiological importance in the metabolism of peptide hormones and is currently being investigated as a target for the treatment of type II diabetes. DPPIV has important functions also in cell adhesion, cellular trafficking, and regulation of T cell activation, which are mediated by functional domains distinct from the catalytic domain (2-5). DPPIV is the most studied member of a growing class of interesting molecules with diverse activities.DPP10 is prominently expressed in the brain as well as adrenal glands and trachea, but its functions remain to be discovered. The human DPP10 gene was recently identified as a candidate for susceptibility to asthma, a common disease of the airways involving atopic inflammation and hyper-responsiveness to various agents (6). Consistent with this report, independent mouse genome screens have...

A leucine heptad repeat is well conserved in voltage-dependent ion channels. Herein we examine the role of the repeat region in Shaker K+ channels through substitution of the leucines in the repeat and through coexpression of normal and truncated products. In contrast to leucine-zipper DNA-binding proteins, we find that the subunit assembly of Shaker does not depend on the leucine heptad repeat. Instead, we report that substitutions of the leucines in the repeat produce large effects on the observed voltage dependence of conductance voltage and prepulse inactivation curves. Our results suggest that the leucines mediate interactions that play an important role in the transduction of charge movement into channel opening and closing.The Shaker gene family (Sh) encodes proteins that produce voltage-dependent K+-selective currents (1-3). Like other voltage-dependent ion channels, Sh channels open and close an aqueous pore by undergoing cotnformational transitions in response to changes in membrane potential. This gating behavior includes the movement of a charged component or voltage sensor (4, 5). Interestingly, mutagenesis of charged residues in the S4 domain (a proposed transmembrane segment that contains four to eight basic residues and is found in virtually all voltage-dependent ion channels including Sh) of the rat II Na' channel showed that it exhibits some of the properties expected for a voltage sensor (6). However, the voltage-dependent gating mechanism remains unclear; in particular, it is not known how movement of the voltage sensor(s) is transduced into the conformational transitions that result in opening and closing of the channel pore.Functional Sh channels are likely to be tetramers since Na+ and Ca2" channels are composed of four homology domains, each roughly equivalent to a single K+ channel subunit (7). Although recent work has shown that Sh channels are multimeric (8), the sites of subunit interaction are unknown. Sh channels contain a conserved leucine heptad repeat (five leucines long) that overlaps two proposed transmembrane segments (S4 and S5); similar motifs are found in Na+ and Ca2+ channels (9) (Fig. 1). Ion-channel leucine heptad repeats are preceded by, and partially overlap, the basic S4 domain (Fig. 1) Deduced amino acid alignments of the leucine-heptadrepeat region. Basic residues in S4 (stars) and leucine residues in the heptad repeat (boxed) were aligned. Amino acids identical to Sh are indicated by dashes. Proposed transmembrane segments S4 and S5 are indicated. Sh (10) is the Drosophila Shaker channel. Other K+ channel sequences are a rat Sh homolog (RCK1) (2), two human Sh homologs (HukI and HukII) (11), and Shab, Shaw, and Shal, which represent other Drosophila K+ channel genes (3). Na and Ca sequences are from the second homology domains of the rat Ila Na' channel and the skeletal muscle dihydropyridine receptor (12), respectively.Since Sh K+ channels are multimeric it suggests that the leucine heptad repeat might act as a site for subunit assembly. In addition, the c...

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Mammalian voltage-activated Shaker K ÷ channels associate with at least three cytoplasmic proteins: Kv101, Kv102 and Kv103. These/3 subnunits contain variable N-termini, which can modulate the inactivation of Shaker ct subunits, but are homologous throughout an aldo-keto reductase core. Human and ferret 133 proteins are identical with rat 101 throughout the core while 102 proteins are not; 102 also contains a shorter N-terminus and has no reported physiological role. We report that human 101 and 103 are derived from the same gene and that 102 modulates the inactivation properties of Kvl.4 ~ subunits.