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

Abstract

Dipeptidyl peptidase-like proteins (DPLs) and Kv-channel interacting proteins (KChIPs) join Kv4 pore-forming subunits to form multi-protein complexes that underlie subthreshold A-type currents (I SA ) in neuronal somatodendritic compartments. Here, we characterize the functional effects and brain distributions of N-terminal variants belonging to the DPL dipeptidyl peptidase 10 (DPP10). In the Kv4.2+KChIP3+DPP10 channel complex, all DPP10 variants accelerate channel gating kinetics; however, the splice variant DPP10a produces uniquely fast inactivation kinetics that accelerates with increasing depolarization. This DPP10a-specific inactivation dominates in coexpression studies with KChIP4a and other DPP10 isoforms. Real-time qRT-PCR and in situ hybridization analyses reveal differential expression of DPP10 variants in rat brain. DPP10a transcripts are prominently expressed in the cortex, whereas DPP10c and DPP10d mRNAs exhibit more diffuse distributions. Our results suggest that DPP10a underlies rapid inactivation of cortical I SA , and the regulation of isoform expression may contribute to the variable inactivation properties of I SA across different brain regions.

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

“…Fig. 2D shows that, as reported previously (7,8), KChIP4a dramatically slows the inactivation kinetics of Kv4.2 currents to an extent that inactivation remains incomplete even after a 1-s-long depolarization. At more depolarized potentials (0 mV and above), the inactivation decay kinetics are clearly double exponential.…”

“…However, when Kv4.2 is coexpressed with both KChIP4a and DPP6-S, the current amplitude is dramatically increased (data not shown), whereas the inactivation kinetics resembles that of Kv4.2 ϩ KChIP4a channels (8). This suggests that DPP6-S and perhaps other DPLPs interacts with Kv4.2 and may be necessary for efficient surface expression of I SA in neurons that express tmKChIPs.…”

“…Although DPP10a overrides KChIP4a at depolarized potential by mediating ultrafast inactivation, at more modest potentials, where neurons typically operate, measurable effects of KChIP4a can still be seen. For example, the influence of KChIP4a on Kv4.2 ϩ DPP10a channels is detectable as an ϳ15-mV depolarizing shift in the G-V relationship and slower recovery from inactivation (8). Although beyond the scope of the present work, it would highly informative to determine the combinatorial effects produced when KChIP2x and KChIP3x are co-expressed in the presence of different DPLPs.…”

“…Indeed, the apparent broad distribution of KISD-containing KChIPs expression in the brain would suggest that such slow Kv4-based A-currents are more widely distributed than previously thought. Two important factors, however, may limit the extent of inactivation slowing produced by these KIS-ing cousins: 1) KISD-containing channel express less well on the cell surface, leading to functional underrepresentation; 2) certain DPLP isoforms, such as DPP10a, may dominantly determine the inactivation kinetics at depolarized potentials even if KISD subunits are present (8). Although DPP10a overrides KChIP4a at depolarized potential by mediating ultrafast inactivation, at more modest potentials, where neurons typically operate, measurable effects of KChIP4a can still be seen.…”

“…In the presence of KChIP4a, KChIP2x, KChIP3x, and KChIP3a, Kv4.2 inactivates with an inverse voltage dependence, where increases in voltage result in decreases in inactivation rate. In contrast, Kv4.2 inactivation accelerates with increasing voltage (8,25). This inverse voltage dependence appears to be characteristic of the Kv4 closed state inactivation mechanism, which becomes increasingly less effective with increasing depolarization (25)(26)(27).…”