Numerous studies suggest that unc-79, unc-80, and NALCN, function in the same biochemical pathway. In both C. elegans and Drosophila, for instance, mutants exhibit altered locomotor behavior (“fainting” in worms and hesitant walking in flies) and have altered responses to anesthetics [10]. In addition, the protein expression of these gene products is interdependent, i.e. disruption of unc-79 or unc-80 also yields lower or absent expression of NALCN orthologs and vice versa, leading to the hypothesis that they function as a complex [10]–[14]. Most compelling is recent data demonstrating that the function of the NALCN protein can be modulated by the peptide neurotransmitters substance P and neurotensin and that the unc-80 gene product is required to mediate this signal transduction pathway [13], [14]. Others have demonstrated in vitro that the M3 muscarinic receptor can activate the NALCN channel [15]. Together, these data indicate that the NALCN channel and associated proteins may be responsible for a ‘slow’ excitation that can be evoked by substance P, neurotensin, acetylcholine or norepinehprine [16]–[18].
