The Somato-Dendritic A-type K+ Channel Complex: A Ménage à Trois

The somato-dendritic subthreshold-operating A-type K + current (I SA) plays a crucial role in neuronal excitability. It regulates spike timing and frequency, dampens the back propagation of action potentials into dendrites and has an important role in dendritic signal processing (Hoffman et al., 1997). Hence, any alteration of I SA current density or gating kinetics could then have important consequences on dendritic integration and plasticity. Kv4 channel protein complexes represent the molecular correlate of the I SA current (Birnbaum et al., 2004; Maffie and Rudy, 2008). Studies in heterologous expression systems have shown that Kv4 pore-forming α subunits interact with two different auxiliary subunits: Kv-channel-interacting proteins (KChIPs) and the dipeptidyl-peptidase-like proteins DPP6 and DPP10 (DPPX). Both auxiliary subunits affect channel gating and trafficking and their co-expression with Kv4 α subunits reca-pitulates the kinetics and gating properties of native I SA. The discovery of Nadal et al. (2003) showing that DPP6 proteins can be co-purified with Kv4.2 K + channel proteins from rat cerebellum and suggesting that they might function as auxiliary subu-nits of the channel complex, opened new interesting perspectives for the role of this structurally-related dipeptidyl aminopeptidase. Indeed, recent studies showed that mutations in the DPP6 gene are associated with human neurological diseases, including amyotrophic lateral sclerosis (ALS), autism and progressive spinal muscular atrophy. DDP6 is a type II transmembrane protein, highly expressed in the nervous system and belonging to the prolyl oligopeptidase family of serine proteases. It consists of a large extracellular C-terminal domain, a single membrane-spanning domain and a short alternatively spliced intracellular N-terminus. DPP6 has a dimeric structure and has lost a catalytic serine residue, suggesting that it is unlikely to function as a dipeptidyl aminopeptidase (Strop et al., 2004). Though biochemical and functional data strongly suggest that DPP6 is an integral component of the Kv4.2 K + channel complex and functions as an auxiliary subunit, the lack of good quality antibod-ies prevented high-resolution localization studies in native brain tissue. In the recent issue of Frontiers, Clark et al. (2008) provide a strong argument supporting the view that DPP6 is an integral part of native Kv4.2 channel complexes (I SA) in the brain. They raised antibodies against the whole extracellular domain of the protein, which was recombinantly expressed in baculovi-rus-infected Sf9 cells. Using this specific tool, they investigated DPP6 distribution in mouse brain and compared it with the distribution of Kv4 proteins (Clark et al., 2008). …