DPP10 Modulates Kv4-mediated A-type Potassium Channels

Abstract

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...

DPP10 splice variants are localized in distinct neuronal populations and act to differentially regulate the inactivation properties of Kv4-based ion channels

“…These results suggest that the single transmembrane segment and the extracellular domains are important for the changes common to all DPP10s. This is consistent with findings by Zagha et al (2005), Ren et al (2005), and Li et al (2005) that showed the transmembrane domain and the surrounding region is sufficient for the DPL interaction with and the modulation of Kv4 channels. The extracellular domain of DPLs, based on C-terminal truncation studies, has been suggested to contribute in stabilizing the Kv4-DPL interaction (Zagha et al, 2005).…”

“…This is consistent with findings by Zagha et al (2005), Ren et al (2005), and Li et al (2005) that showed the transmembrane domain and the surrounding region is sufficient for the DPL interaction with and the modulation of Kv4 channels. The extracellular domain of DPLs, based on C-terminal truncation studies, has been suggested to contribute in stabilizing the Kv4-DPL interaction (Zagha et al, 2005). Our lab also has observed that, upon cMyc-tagging of the DPP10 distal C-terminus, the coimmunoprecipitation between DPP10 and Kv4.2 is diminished, consistent with role of the extracellular domain in complex stabilization (H Jerng, unpublished observations).…”

“…Both tagged DPP10 variants produce leftward shifts in conductance-voltage relationships, leftward shifts in steady-state inactivation, and accelerated recovery from inactivation. Similar to DPP10 facilitating the trafficking of Kv4 channels to the cell surface (Jerng et al, 2004a;Zagha et al, 2005), DPP10a/HA* and DPP10c/cMyc* both also dramatically enhance the surface expression of ΔN2-40 channels (DPP10a/HA*: ~17-fold; DPP10c/ cMyc*: ~19-fold).…”

“…Recent studies in heterologous expression systems have suggested that the combined effects of Kv4 modulatory β-subunits, K channel-interacting proteins (KChIPs) and dipeptidyl peptidaselike (DPL) proteins, are required to produce functional A-type currents from Kv4 ternary channel complexes that resemble native neuronal I SA (Nadal et al, 2003;Jerng et al, 2005). DPLs include the genetically-related dipeptidyl peptidase 6 (DPP6; also known as BSPL, DPL1, and DPPX) and dipeptidyl peptidase 10 (DPP10; also known as KIAA1492, DPRP3, DPL2, and DPPY) (Wada et al, 1992;de Lecea et al, 1994;Nagase et al, 2000;Chen et al, 2003;Qi et al, 2003;Nadal et al, 2003;Jerng et al, 2004a;Zagha et al, 2005;Ren et al, 2005). When expressed alone, Kv4 channels are transported poorly to the cell surface and express kinetic properties very different from those of native I SA channels (Shibata et al, 2003; reviewed by Jerng et al, 2004b).…”

Unanticipated Region- and Cell-Specific Downregulation of Individual KChIP Auxiliary Subunit Isotypes in Kv4.2 Knock-Out Mouse Brain

“…These channels are formed by four Kv4 ␣ subunits in association with cytoplasmic KChIP (An et al, 2000;Rhodes et al, 2004) and/or transmembrane DPPX (Nadal et al, 2003) or dipeptidylpeptidase 10 (Jerng et al, 2004a;Zagha et al, 2005) auxiliary subunits. Coexpression of KChIP1-KChIP3, but not KChIP4, with Kv4 ␣ subunits in heterologous cells dramatically increases surface expression and slows the turnover rate of Kv4 protein, and slows the inactivation kinetics and speeds the rate of recovery from inactivation of Kv4 channels (An et al, 2000;Shibata et al, 2003;Jerng et al, 2004b).…”