KCNQ‐SMIT complex formation facilitates ion channel‐solute transporter cross talk

Voltage‐gated potassium channels formed by KCNQ2 and KCNQ3 are essential for normal neuronal excitability. KCNQ2/3 channel activity is augmented in vivo by phosphatidylinositol 4,5‐bisphosphate (PIP 2 ), which is generated from myo ‐inositol, an osmolyte transported into cells by sodium‐dependent myo ‐inositol transporters (SMITs). Here, we discovered that KCNQ2/3 channels isoform‐specifically colocalize with SMIT1 and SMIT2 at sciatic nerve nodes of Ranvier and in axon initial segments, and form channel–transporter complexes in vitro and in vivo . KCNQ2/3 coexpression protected SMIT1 activity from the otherwise inhibitory effects of cellular depolarization imposed by elevating extracellular [K + ], and KCNQ2 was required for potentiation of SMIT activity by myo ‐inositol preincubation. Cytoskeletal disruption, which speeds PIP 2 dispersion, attenuated potentiation of KCNQ2/3 currents by SMIT1‐mediated myo ‐inositol uptake, suggesting close channel–transporter juxtaposition ensures KCNQ2/3 exposure to locally high myo ‐inositol‐derived PIP 2 concentrations. Thus, KCNQ2/3‐SMIT1/2 coassembly permits cross talk via physical interaction, and may also be required for optimal, reciprocal indirect regulation via membrane potential and PIP 2 , especially within the specialized architecture of axons.—Neverisky, D. L., Abbott, G. W. KCNQ‐SMIT complex formation facilitates ion channel‐solute transporter cross talk. FASEB J. 31, 2828–2838 (2017). www.fasebj.org