Flexible Stoichiometry: Implications for KCNQ2- and KCNQ3-Associated Neurodevelopmental Disorders

Abstract

KCNQ2 and KCNQ3 pathogenic channel variants have been associated with a spectrum of developmentally regulated diseases that vary in age of onset, severity, and whether it is transient (i.e., benign familial neonatal seizures) or long-lasting (i.e., developmental and epileptic encephalopathy). KCNQ2 and KCNQ3 channels have also emerged as a target for novel antiepileptic drugs as their activation could reduce epileptic activity. Consequently, a great effort has taken place over the last 2 decades to understand the mechanisms that control the assembly, gating, and modulation of KCNQ2 and KCNQ3 channels. The current view that KCNQ2 and KCNQ3 channels assemble as heteromeric channels (KCNQ2/3) forms the basis of our understanding of KCNQ2 and KCNQ3 channelopathies and drug design. Here, we review the evidence that supports the formation of KCNQ2/3 heteromers in neurons. We also highlight functional and transcriptomic studies that suggest channel composition might not be necessarily fixed in the nervous system, but rather is dynamic and flexible, allowing some neurons to express KCNQ2 and KCNQ3 homomers. We propose that to fully understand KCNQ2 and KCNQ3 channelopathies, we need to adopt a more flexible view of KCNQ2 and KCNQ3 channel stoichiometry, which might differ across development, brain regions, cell types, and disease states.

Keywords: Autism; Epilepsy; KCNQ2; KCNQ3; Potassium channels.

Fig. 1.

(A) Example of KCNQ2/3 mediated currents expressed in HEK293T cells at room and at near physiological temperature. Notice the slow activation kinetics independent of temperature. Bottom panel shows summary of conductance-to-voltage relationship of KCNQ2/3 current at room and near physiological temperatures. Independent of temperature KCNQ2/3 currents start activating at ~ −60 to −50 mV. The data were fit with a Boltzmann equation (unpublished data, Tzingounis).

Fig. 2.

Developmetal expression of Kcnq2 and Kcnq3 mRNA in dentate gyrus of the hippocampus. Panels show t-distributed stochastic neighbor embedding (t-SNE) plots of dentate gyrus cell types across development. Each dot point represents a cell expressing a designated mRNA. Panels show the scRNA data for Kcnq2 and Kcnq3 mRNA. The illustration depicts the developmental trajectory of the different cell types identified in Dentate gyrus. In particular, the t-SNE represents visualisation of 24,185 cells from mice of various ages, perinatal (E16.5–P5), juvenile (P18–P23), and adult (P120–P132) mice. Data for this illustration obtained from http://linnarssonlab.org/dentate/. See Hochgerner et al (2018) [59] for details. GC:granule cells, Pyr:Pyramidal neurons, CRs: Cajal-Retzius cells, OPC:oligodendrocyte progenitor cells, NFOL: newly formed oligodenrdocytes, MOL: Mature oligodendrocytes, RG: radial glial.