Abstract
Potassium channels form physical complexes with solute transporters in vivo, yet little is known about their range of possible signaling modalities and the underlying mechanisms. The KCNQ2/3 potassium channel, which generates neuronal M-current, is voltage-gated and its activity is also stimulated by binding of various small molecules. KCNQ2/3 forms reciprocally regulating complexes with sodium-coupled myo-inositol transporters (SMITs) in mammalian neurons. Here, we report that the neurotransmitter γ-aminobutyric acid (GABA) and other small molecules directly regulate myo-inositol transport in rat dorsal root ganglia, and by human SMIT1-KCNQ2/3 complexes in vitro, by inducing a distinct KCNQ2/3 pore conformation. Reciprocally, SMIT1 tunes KCNQ2/3 sensing of GABA and related metabolites. Ion permeation and mutagenesis studies suggest that SMIT1 and GABA similarly alter KCNQ2/3 pore conformation but via different KCNQ subunits and molecular mechanisms. KCNQ channels therefore act as chemosensors to enable co-assembled myo-inositol transporters to respond to diverse stimuli including neurotransmitters, metabolites and drugs.
Highlights
Potassium channels form physical complexes with solute transporters in vivo, yet little is known about their range of possible signaling modalities and the underlying mechanisms
As we previously found that KCNQ2/3 channels co-localize with SMIT1 in rodent neurons and co-assemble with SMIT1 in vitro[14], we first quantified the effects of GABA on myo-inositol uptake of whole dorsal root ganglia (DRG) isolated from postnatal day 8 rats
We showed earlier that complexes formed by SMIT1 and heteromeric mutant W236L–KCNQ2/W265L–KCNQ3 channels do not respond to GABA (Fig. 1e) which is consistent with the role of the segment 5 (S5) W residues in GABA binding
Summary
Potassium channels form physical complexes with solute transporters in vivo, yet little is known about their range of possible signaling modalities and the underlying mechanisms. The KCNQ2/3 potassium channel, which generates neuronal M-current, is voltage-gated and its activity is stimulated by binding of various small molecules. KCNQ2/3 forms reciprocally regulating complexes with sodium-coupled myo-inositol transporters (SMITs) in mammalian neurons. We report that the neurotransmitter γ-aminobutyric acid (GABA) and other small molecules directly regulate myo-inositol transport in rat dorsal root ganglia, and by human SMIT1-KCNQ2/3 complexes in vitro, by inducing a distinct KCNQ2/3 pore conformation. KCNQ2/3 channels are muscarinic acetylcholine receptor-regulated, non-inactivating, and open at relatively hyperpolarized membrane potentials They are uniquely placed to regulate neuronal excitability. The primary inhibitory neurotransmitter in higher animals, γ-aminobutyric acid (GABA) is well-known for its essential role in inhibitory neurotransmission, whereby it activates canonical GABA receptors including GABAA receptors (GABAARs), which are ligand-gated, chloride-selective channels that open to suppress neuronal excitability[6].
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