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

Abstract

Voltage-gated potassium channels formed by KCNQ2 and KCNQ3 are essential for normal neuronal excitability. KCNQ2/3 channel activity is augmented by phosphatidylinositol 4,5-bisphosphate (PIP), which is generated from -inositol, an osmolyte transported into cells by sodium-dependent-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 and 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 -inositol preincubation. Cytoskeletal disruption, which speeds PIP dispersion, attenuated potentiation of KCNQ2/3 currents by SMIT1-mediated -inositol uptake, suggesting close channel-transporter juxtaposition ensures KCNQ2/3 exposure to locally high-inositol-derived PIP concentrations. Thus, KCNQ2/3-SMIT1/2 coassembly permits cross talk physical interaction, and may also be required for optimal, reciprocal indirect regulation membrane potential and PIP, especially within the specialized architecture of axons.-Neverisky, D. L., Abbott, G. W. KCNQ-SMIT complex formation facilitates ion channel-solute transporter cross talk.

Chansporter complexes in cell signaling

“…We found that not only is SMIT1-transported myoinositol able to generate sufficient PIP 2 to modulate KCNQ2/3 activity, as reported by Dai et al but also that SMIT1 forms physical complexes with KCNQ2, and that KCNQ2 and KCNQ3 each colocalize with SMIT1 and/or SMIT2 in axon initial segments and sciatic nerve nodes of Ranvier [130]. Colocalization/ coassembly of KCNQ2/3 channels with SMIT1/2 may facilitate the channel being able exploit locally high PIP 2 concentrations generated from SMIT1/2-transported myo-inositol, an hypothesis supported by previous studies showing that PIP 2 diffusion is quite slow in the presence of intact cytoskeleton [131], and our finding that disruption of the cytoskeleton impairs the ability of SMIT1 to potentiate KCNQ2/3 current after 3 h of incubation in 1 mM myo-inositol [130]. Reciprocally, KCNQ2/3 channels protect SMIT1 activity from the otherwise inhibitory effect of cellular depolarization via high extracellular K + [130].…”

“…Thus, KCNQs can communicate information about the membrane potential of the cell to SMIT1 via either S4 position or channel activity, or perhaps both. Thus, we found that KCNQ2/3 coexpression enabled SMIT1 to maintain its transport activity during cellular depolarization, whereas without KCNQ2/ 3, cellular depolarization lowered SMIT1 transport activity [130]. In contrast, locking the KCNQ1 S4 open (to mimic aspects of cell depolarization without actually depolarizing the cell) inhibited activity of coexpressed SMIT1 [110].…”

“…Because PIP 2 diffusion within the membrane is quite slow, KCNQ‐SMIT proximity could help ensure locally high PIP 2 concentrations for activation of KCNQ channels. This may be especially important in constrained spaces such as axons . Biosensor sharing . Channels and transporters might coassemble because it is advantageous to exploit one another's biosensory capabilities.…”

Control of Slc7a5 sensitivity by the voltage-sensing domain of Kv1 channels

“…At present, we have not determined whether there is reciprocal modulation of Slc7a5 function by Kv channels. However, this possibility will continue to be explored, as certain combinations of Kv7 channels and myo-inositol transporters exhibit mutual regulation (Abbott et al, 2014;Manville et al, 2017;Neverisky and Abbott, 2017) .…”

Potassium channels act as chemosensors for solute transporters

“…(or SMIT2) by providing a substrate for local production of PIP 2 . In addition, SMIT1 co-assembly alters the pharmacology of KCNQ2 and KCNQ2/3 channels 13,14 .…”