Immunohistochemical localization of DPP10 in rat brain supports the existence of a Kv4/KChIP/DPPL ternary complex in neurons

Abstract

Subthreshold A-type K(+) currents (ISA s) have been recorded from the cell bodies of hippocampal and neocortical interneurons as well as neocortical pyramidal neurons. Kv4 channels are responsible for the somatodendritic ISA s. It has been proposed that neuronal Kv4 channels are ternary complexes including pore-forming Kv4 subunits, K(+) channel-interacting proteins (KChIPs), and dipeptidyl peptidase-like proteins (DPPLs). However, colocalization evidence was still lacking. The distribution of DPP10 mRNA in rodent brain has been reported but its protein localization remains unknown. In this study, we generated a DPP10 antibody to label DPP10 protein in adult rat brain by immunohistochemistry. Absent from glia, DPP10 proteins appear mainly in the cell bodies of DPP10(+) neurons, not only at the plasma membrane but also in the cytoplasm. At least 6.4% of inhibitory interneurons in the hippocampus coexpressed Kv4.3, KChIP1, and DPP10, with the highest density in the CA1 strata alveus/oriens/pyramidale and the dentate hilus. Colocalization of Kv4.3/KChIP1/DPP10 was also detected in at least 6.9% of inhibitory interneurons scattered throughout the neocortex. Both hippocampal and neocortical Kv4.3/KChIP1/DPP10(+) inhibitory interneurons expressed parvalbumin or somatostatin, but not calbindin or calretinin. Furthermore, we found colocalization of Kv4.2/Kv4.3/KChIP3/DPP10 in neocortical layer 5 pyramidal neurons and olfactory bulb mitral cells. Together, although DPP10 is also expressed in some brain neurons lacking Kv4 (such as parvalbumin- and somatostatin-positive Golgi cells in the cerebellum), colocalization of DPP10 with Kv4 and KChIP at the plasma membrane of ISA -expressing neuron somata supports the existence of Kv4/KChIP/DPPL ternary complex in vivo.

Kv4.2 and Accessory Dipeptidyl Peptidase-like Protein 10 (DPP10) Subunit Preferentially Form a 4:2 (Kv4.2:DPP10) Channel Complex

“…DPP6 is also expressed in the hippocampal mossy fibers where Kv4.2 is absent (22) suggesting that the expression of Kv4.2 and DPP6 do not always overlap. DPP10 is also widely co-expressed in many brain regions with Kv4.2 and/or Kv4.3 (35). Interestingly, the sublocalization of DPP10 does not perfectly overlap with Kv4 and KChIP.…”

“…Interestingly, the sublocalization of DPP10 does not perfectly overlap with Kv4 and KChIP. DPP10 is expressed mainly in the soma, whereas Kv4.3 and KChIP1 are expressed both in the soma and the dendrites of the hippocampus and the neocortex (35). This means that the stoichiometry of the ternary complex may be different depending on the subcellular location.…”

“…Is the Stoichiometry of the Kv4-KChIP-DPP Ternary Complex Variable under Physiological Conditions?-It is known that Kv4 forms a ternary complex with DPP and KChIP in the brain (17,35,60,64). In a previous study, we revealed that the stoichiometry of the Kv4.2-KChIP4 complex is variable, with no specific preference, and changes depending on the expression level of KChIP (50).…”

“…Kv4, DPP, and KChIP form a ternary complex in neurons (35,60,61). To examine whether the co-expression of KChIP4 affects the stoichiometry of the Kv4.2-DPP10 complex, Kv4.2-mCherry, mEGFP-DPP10, and KChIP4 were all co-expressed (Fig.…”

“…DPP6 has been implicated in neuropsychiatric pathologies including autism spectrum disorders (30,31), mental retardation (32), and amyotrophic lateral sclerosis (33,34). DPP10 is also broadly expressed in the brain including the hippocampus, neocortex, cerebellum, and main olfactory bulb, where Kv4-KChIP-DPP form a ternary complex (35). DPP10 is also implicated in neuropsychiatric diseases such as autism (30,36) and Alzheimer disease (37).…”