A Leak K⁺Channel TWK-40 Regulates Rhythmic Motor Program inC. elegans

Abstract

Background: potassium (K+) leak currents, conducted by two-pore domain K+ (K2P) channels, are critical for the stabilization of the membrane potential. The effect of K2P channels on motor rhythm remains enigmatic. We show here a K2P TWK-40 regulates the rhythmic defecation motor program (DMP) in Caenorhabditis elegans. Disrupting TWK-40 suppresses the expulsion defects of nlp-40 and aex-2 mutants. By contrast, a gain-of-function (gf) mutant of twk-40 significantly reduces the expulsion frequency per DMP cycle. In situ whole-cell patch clamping demonstrates that TWK-40 forms an outward currents that hyperpolarize the resting membrane potential of DVB neuron. In addition, TWK-40 substantially contributes to the rhythmic activity of the DVB. Specifically, DVB Ca2+ oscillations exhibit obvious defects in twk-40 mutants. Expression of TWK-40(gf) in DVB recapitulates the expulsion deficiency of the twk-40(gf) mutant, and inhibits DVB Ca2+ oscillations in both wild-type and twk-40(lf) animals. Moreover, DVB innervated enteric muscles also exhibit rhythmic Ca2+ defects. Taken together, these results demonstrate that the TWK-40 is an essential inhibitor of DMP, thus revealing a cellular mechanism by funtional K2P channel of rhythmic motor activity.

Constitutive sodium permeability in aC. eleganstwo-pore domain potassium channel

“…For example, flaccid paralysis is observed in gof mutants of the muscle TWK-18 (Kunkel et al, 2000) or the neuronal TWK-40 channel (Zhou et al, 2022). As expected, gof mutations in TWK-18 or TWK-40 give rise to an increased outward current and a decrease of the resting membrane potential (Ben Soussia et al, 2019; Yue et al, 2022). In contrast, we have shown here that UNC-58 carries an inward current and that hyperactivation of UNC-58 increases the resting membrane potential of muscle cells in vivo .…”

“…For instance, gain-of-function mutants of K2P channels expressed in skeletal muscles, such as SUP-9, TWK-18 or TWK-28 (Ben Soussia et al, 2019; de la Cruz et al, 2003; Kunkel et al, 2000; Peysson et al, 2023) cause muscle relaxation and a flaccid paralysis. Increased activity of K2P channels expressed in neurons of the motor circuitry, such as TWK-2, TWK-7 or TWK-40 (Yue et al, 2022; Zhou et al, 2022) similarly results in dramatic locomotor impairment and relaxed posture.…”

Differential modulation of C. elegans motor behavior by NALCN and two-pore domain potassium channels

“…elegans motor behavior and suggest that the behavioral effects of twk-40 might be associated with its neuron-specific expression and functional differentiation of transcript isoforms. Two recent studies further analyzed TWK-40 functions in regulating the resting membrane potentials and activities of AVA and DVB neurons [ 81 , 82 ]. We also uncovered potential behavioral effects of five other K2P genes and provide genetic evidence that some K2Ps and NALCN can oppositely affect different aspects of C .…”