Transient subthreshold-activating somato-dendritic A-type K(+) currents (I(SA)s) have fundamental roles in neuronal function. They cause delayed excitation, influence spike repolarization, modulate the frequency of repetitive firing, and have important roles in signal processing in dendrites. We previously reported that DPPX proteins are key components of the channels mediating these currents (Kv4 channels) (Nadal, M.S., Ozaita, A., Amarillo, Y., Vega-Saenz, E., Ma, Y., Mo, W., Goldberg, E.M., Misumi, Y., Ikehara, Y., Neubert, T.A., Rudy, B., 2003. The CD26-related dipeptidyl aminopeptidase-like protein DPPX is a critical component of neuronal A-type K+ channels. Neuron 37, 449-461). The DPPX gene encodes alternatively spliced transcripts that generate single-spanning transmembrane proteins with a short, divergent intracellular domain and a large extracellular domain. We characterized the modulatory effects on Kv4.2-mediated currents and the rat brain distribution of three splice variants of the DPPX subfamily of proteins. These three splice isoforms--DPPX-S, DPPX-L, and DPPX-K--are expressed in adult rat brain and modify the voltage dependence and kinetic properties of Kv4.2 channels expressed in Xenopus oocytes. Analysis of a deletion mutant that lacks the variable N-terminus showed that the N-terminus is not necessary for the modulation of Kv4 channels. Using in situ hybridization analysis, we found that the three splice variants are prominently expressed in brain regions where Kv4 subunits are also expressed. DPPX-K and DPPX-S mRNAs have a widespread distribution, whereas DPPX-L transcripts are concentrated in few specific areas of the rat brain. The emerging diversity of DPPX splice variants, differing only in the N-terminus of the protein, opens up intriguing possibilities for the modulation of Kv4 channels.