DPP10 modulates Kv4-mediated A-type potassium channels.
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.
Zagha
Edward
E
Department of Physiology and Neuroscience, New York University School of Medicine, New York, New York 10016.
Ozaita
Andres
A
Chang
Su Ying
SY
Nadal
Marcela S
MS
Lin
Udele
U
Saganich
Michael J
MJ
McCormack
Tom
T
Akinsanya
Karen O
KO
Qi
Shu Y
SY
Rudy
Bernardo
B
D000595:Amino Acid Sequence; D000818:Animals; D019921:Biotinylation; D015152:Blotting, Northern; D001921:Brain / Q000378:metabolism; D016466:CHO Cells; D002462:Cell Membrane / Q000378:metabolism; D002490:Central Nervous System / Q000378:metabolism; D006224:Cricetinae; D004152:Dipeptidyl-Peptidases and Tripeptidyl-Peptidases / Q000378:metabolism / Q000502:physiology*; D004594:Electrophysiology; D006801:Humans; D015151:Immunoblotting; D007150:Immunohistochemistry; D047468:Immunoprecipitation; D017403:In Situ Hybridization; D007700:Kinetics; D013058:Mass Spectrometry; D051379:Mice; D008810:Mice, Inbred C57BL; D008958:Models, Molecular; D008969:Molecular Sequence Data; D009419:Nerve Tissue Proteins / Q000378:metabolism / Q000502:physiology; D009474:Neurons / Q000378:metabolism; D010455:Peptides / Q000737:chemistry; D015221:Potassium Channels / Q000378:metabolism / Q000502:physiology; D024642:Potassium Channels, Voltage-Gated / Q000378:metabolism*; D011487:Protein Conformation; D017434:Protein Structure, Tertiary; D012313:RNA / Q000737:chemistry; D051381:Rats; D017207:Rats, Sprague-Dawley; D011993:Recombinant Fusion Proteins / Q000737:chemistry; D017386:Sequence Homology, Amino Acid; D051672:Shal Potassium Channels; D013997:Time Factors; D014162:Transfection
D009419:Nerve Tissue Proteins; D010455:Peptides; D015221:Potassium Channels; D024642:Potassium Channels, Voltage-Gated; D011993:Recombinant Fusion Proteins; D051672:Shal Potassium Channels; D012313:RNA; C476879:DPP10 protein, human; C572637:DPP10 protein, mouse; C557320:DPP6 protein, rat; D004152:Dipeptidyl-Peptidases and Tripeptidyl-Peptidases