KCNQ1, KCNE2, and Na ⁺ -Coupled Solute Transporters Form Reciprocally Regulating Complexes That Affect Neuronal Excitability

Abstract

Na+-coupled solute transport is crucial for the uptake of nutrients and metabolic precursors, such as myo-inositol, an important osmolyte and precursor for various cell signaling molecules. Here, we found that various solute transporters and potassium channel subunits formed complexes and reciprocally regulated each other in vitro and in vivo. Global metabolite profiling revealed that mice lacking KCNE2, a K+ channel β subunit, showed a reduction in the myo-inositol concentration in cerebrospinal fluid (CSF) but not in serum. Increased behavorial responsiveness to stress and seizure susceptibility in Kcne2−/− mice were alleviated by injections of myo-inositol. Suspecting a defect in myo-inositol transport, we found that KCNE2 and KCNQ1, a voltage-gated potassium channel α subunit, colocalized and coimmunoprecipitated with SMIT1, a Na+-coupled myo-inositol transporter, in the choroid plexus epithelium. Heterologous coexpression demonstrated that myo-inositol transport by SMIT1 was augmented by coexpression of KCNQ1 but inhibited by coexpression of both KCNQ1 and KCNE2, which form a constitutively active, heteromeric K+ channel. SMIT1 and the related transporter SMIT2 were also inhibited by a constitutively active mutant form of KCNQ1. The activity of KCNQ1 and KCNQ1-KCNE2 were augmented by SMIT1 and the glucose transporter SGLT1, but suppressed by SMIT2. Channel-transporter signaling complexes may be a widespread mechanism to facilitate solute transport and electrochemical crosstalk.

Osmoregulatory inositol transporter SMIT1 modulates electrical activity by adjusting PI(4,5)P2levels

“…In addition, we found that the voltage sensitivity of KCNQ2/3 channels became enhanced. This was not found for KCNQ1 or KCNQ1+KCNE2 channels using similar treatments (35). Reminiscent of the previous research using overexpression of PI(4)P-5 kinase to increase PI(4,5)P 2 levels (62-64), here we confirmed that the voltage sensitivity of KCNQ2/3 can be regulated by manipulating PI(4,5)P 2 levels.…”

“…A recent study reported that SMIT1 and KCNQ1 channels with the auxiliary channel subunit KCNE2 show a reciprocal regulation in the brain, suggested to be due to formation of direct channel-transporter complexes (35). Our findings do not exclude such channel-transporter complexes for KCNQ2/3.…”

“…We supplemented the culture medium with an additional 100 μM myo-inositol for overnight incubation. The final concentration of myo-inositol is within the physiological range in serum (35). The myo-inositol was never present in the bath solution during recordings.…”

The Sodium/Iodide Symporter (NIS): Molecular Physiology and Preclinical and Clinical Applications

“…These findings have led to the discovery that thyroidal NIS function is also regulated by direct cross talk between NIS and a K + channel. Interestingly, this was the first interaction reported between a channel and a transporter, and it was followed by the discovery of another physiologically relevant interaction between KCNQ1 and KCNE2 and the Na + -coupled myoinositol transporter, a member of the same family as NIS found in the choroid plexus of mice (47). These studies make it clear that channels and transporters do not necessarily function in isolation but, instead, they often regulate each other (48).…”

The KCNE2 K+ channel regulatory subunit: Ubiquitous influence, complex pathobiology

“…We noticed that Kcne2 −/− mice are somewhat prone to handling-induced seizures, and found that they have an increased susceptibility to pentylenetetrazole-induced seizures, showing shorter latency to first seizure, increased seizure severity and increased mortality compared to their wild-type littermates 55 . KCNE2 is reportedly expressed in neuronal populations, as judged by in situ hybridization 56 , but we could not detect KCNE2 protein in mouse neurons by immunohistochemistry 57 .…”