The CD26-Related Dipeptidyl Aminopeptidase-like Protein DPPX Is a Critical Component of Neuronal A-Type K+ Channels

Abstract

Subthreshold-activating somatodendritic A-type potassium channels have fundamental roles in neuronal signaling and plasticity which depend on their unique cellular localization, voltage dependence, and kinetic properties. Some of the components of A-type K(+) channels have been identified; however, these do not reproduce the properties of the native channels, indicating that key molecular factors have yet to be unveiled. We purified A-type K(+) channel complexes from rat brain membranes and found that DPPX, a protein of unknown function that is structurally related to the dipeptidyl aminopeptidase and cell adhesion protein CD26, is a novel component of A-type K(+) channels. DPPX associates with the channels' pore-forming subunits, facilitates their trafficking and membrane targeting, reconstitutes the properties of the native channels in heterologous expression systems, and is coexpressed with the pore-forming subunits in the somatodendritic compartment of CNS neurons.

Quantitative proteomics of the Cav2 channel nano-environments in the mammalian brain

“…So far, however, experimental procedures enabling unbiased and comprehensive access to the environment of membrane proteins have been missing or have just begun to evolve (17)(18)(19)(20)(21)(22)(23)34).…”

“…Antibody-based affinity purification (AP) combined with quantitative MS is a target-directed approach, which, theoretically, allows for strong enrichment of both target proteins and more stably associated partners with tight control of specificity and interaction stringency (16). In fact, AP-based proteomics were successfully used for identification of accessory subunits and regulators of various ion-channel proteins (17)(18)(19)(20)(21)(22)(23). Notwithstanding, there remain several sources of error that are aggravated considerably when approaching protein networks such as those comprising nanoenvironments.…”

Multiple Kv Channel-interacting Proteins Contain an N-terminal Transmembrane Domain That Regulates Kv4 Channel Trafficking and Gating

“…To compare the inactivation kinetics, we used the time when half of the peak current is inactivated (half-inactivation time) since inactivation kinetics of Kv4.2 channels in the presence of various KChIP subunits in this study cannot be adequately fit with the same number of exponential functions. The half-inactivation times for non-KISD-containing KChIPs range from around 50 to 100 ms (at ϩ40 mV: Kv4.2 ϩ KChIP4b-L, 87 ϩ 4.5 ms (n ϭ 5); Kv4.2 ϩ KChIP3a, 104 ϩ 2.4 ms (n ϭ 8); and published values for Xenopus expression of Kv4.2 ϩ KChIP1, 54 ϩ 5.6 ms, and Kv4.2 ϩ KChIP2, ϳ47.9 ms (from single exponential fits) (3,24). These results indicate that among non-KISD-containing KChIP variants, KChIP3a and KChIP4b-L mediates slower inactivation kinetics, and the functional effects of the N-terminal KISD can be appreciated by comparison with either of these variants.…”

Modulation of the Voltage-gated Potassium Channel (Kv4.3) and the Auxiliary Protein (KChIP3) Interactions by the Current Activator NS5806

“…In neurons and cardiomyocytes the Kv4 subfamily of voltagegated K ϩ channels regulate the fast-inactivating components of the I SA and I TO currents, respectively (5). These channels form octameric transmembrane complexes with accessory subunits such as potassium channel interacting proteins (KChIPs) 2 (6), dipeptidyl peptidases (7), and Kv␤ proteins (8). Interaction of KChIP2 with Kv4 channels in heart results in an increase in current density, acceleration of recovery from inactivation, and slower inactivation kinetics (6).…”