Novel pharmacological modulation of dystonic phenotypes caused by a gain-of-function mutation in the Na+ leak-current channel

Abstract

The Na+ leak-current channel (NALCN) regulates the resting membrane potential in excitable cells, thus determining the likelihood of depolarization in response to incoming signals. Gain-of-function (gf) mutations in this channel are associated with severe dystonic movement disorders in man. Currently, there are no known pharmacological antagonists or selective modulators of this important channel. A gain-of-function mutation in NALCN of C. elegans [known as unc-77(e625)] causes uncoordinated, hyperactive locomotion. We hypothesized that this hyperactive phenotype can be rescued with pharmacological modulators. Here, we summarize the results of targeted drug screening aimed at identification of drugs that corrected locomotion deficits in unc-77(e625) animals. To assay hyperactive locomotion, animals were acutely removed from food and characteristic foraging movements were quantified. Drug screening revealed that 2-aminoethoxydiphenyl borate (2-ABP), nifedipine, nimodipine, flunarizine and ethoxzolamide significantly decreased abnormal movements in unc-77(e625) animals. 2-APB also corrected egg release and coiling deficits in this strain. In addition, serotonin and dopamine both reduced hyperactive locomotion, consistent with regulatory interactions between these systems and the NALCN. 2-APB induced movement phenotypes in wild-type animals that faithfully mimicked those observed in NALCN knockout strains, which suggested that this drug may directly block the channel. Moreover, 2-APB and flunarizine showed significant structural similarities suggestive of overlap in their mode of action. Together, these studies have revealed new insights into regulation of NALCN function and led to the discovery of a potential pharmacological antagonist of the NALCN.

Candidate risk genes for bipolar disorder are highly conserved during evolution and highly interconnected

“…This extended pathway has been implicated in BPD 49,50 and includes pharmacological targets of lithium – the gold standard drug for treatment 49 . We draw attention to syntenic block (#8) with NALCN because loss of function in this gene is associated with slow locomotion and reduced appetite/foraging, whereas gain‐of‐function mutations cause hyperactivity and enhanced foraging 51 . We can imagine that oscillations in the function of this channel due to regulatory input (eg, downstream of FGF14) could contribute to some of the dramatic behavioral shifts typical of BPD.…”

Evolutionary conservation of putative suicidality-related risk genes that produce diminished motivation corrected by clozapine, lithium and antidepressants

“…However, we typically evaluated two or more from a single class, for example clozapine and loxapine (antipsychotics) and amitriptyline, amoxapine and imipramine (antidepressants), there was some pharmacological overlap (e.g., anticholinergic activity), and the drugs are structurally quite similar ( Supplementary Figure 3 ). Selective actions of the drugs are indicated by the fact that no discernible effects on locomotion were observed for clozapine, loxapine and amitriptyline in wild-type animals ( 40 ), and clozapine and lithium did not affect the movement phenotype of another mutant – unc-77(e625) ( 68 ). Moreover, the simplicity of C. elegans means there may be a limited number of mechanisms – possibly interconnected – that mediate immobility across the various mutants in response to food deprivation.…”

Case Report: A de novo Variant in NALCN Associated With CLIFAHDD Syndrome in a Chinese Infant

“…To date, there were no efficient treatments for CLIFAHDD, except for symptomatic treatments, such as clonazepam for seizures ( 24 ), acetazolamide for episodic ataxia ( 16 ), and surgical procedures for arthrogryposis ( 27 ). A 2-aminoethoxydiphenyl borate and a flunarizine could rescue the hyperactive phenotype of C. elegans caused by NALCN gain-of-function variants or it might serve as a direct blocker of the channel ( 28 ). However, further validation was needed for clinical implementation.…”