["Acta Physiologica, Volume 242, Issue 6, June 2026. ", "\nABSTRACT\n\nAim\nThe alkali cation/proton exchanger NHE6/SLC9A6 regulates luminal pH homeostasis and trafficking of recycling endosomes in most tissues, especially neurons. Loss‐of‐function mutations in NHE6 cause Christianson Syndrome, an X‐linked neurodevelopmental and neurodegenerative disorder; however, the underlying molecular and cellular mechanisms remain unclear. Here, we describe a new role for NHE6 as a scaffolding platform for recruiting and delivering signaling molecules to the plasma membrane.\n\n\nMethods\nThe yeast two‐hybrid system was used to screen a human brain cDNA library for proteins that bind to the cytoplasmic C‐terminus of NHE6.\n\n\nResults\nCyclin‐dependent kinase 5 (CDK5) was identified as a putative interacting partner. CDK5 is widely expressed and phosphorylates diverse proteins involved in vital processes, including receptor signaling, cytoskeletal organization, endocytosis, exocytosis, and apoptosis. Formation of a NHE6/CDK5 complex was confirmed by biochemical assays and microscopy using Chinese hamster ovary AP‐1 and human neuroblastoma SH‐SY5Y cells. CDK5, in a complex with its activator subunit p35/CDK5R1, did not directly phosphorylate or regulate the membrane trafficking of NHE6. By contrast, NHE6 expression enhanced the localization of CDK5 and p35 to endosomal‐ and plasmalemmal‐enriched membrane fractions and elevated cell surface accumulation of the CDK5‐regulated transient receptor potential V1 (TRPV1) cation channel.\n\n\nConclusions\nThese data indicate that NHE6, aside from its main pH‐regulatory function, can act concomitantly as a scaffold for recruitment of CDK5/p35 to endosomes and the plasma membrane where the kinase is now primed to activate neighboring effectors important for cell function.\n\n"]