, 2010). The two pathways can also act synergistically on NALCN. For example, the reduction of [Ca2+]e to 0.1 mM, or the application of SP, alone elicits ∼40 pA inward current. Simultaneous application of these stimuli induces an ∼400 pA current that is much larger than the sum of the two currents (Figure 5). NALCN channels that lack the C-terminal amino acids do not display this synergism (Lu et al., 2010). A similar synergistic effect of [Ca2+]e reduction and the activation of Src kinase

was also observed in the excitation of neurons, in which [Ca2+]i is “paradoxically” increased by decreasing [Ca2+]e (Burgo et al., 2003). Whether these two pathways influence distinct parameters such as the number of available channels (N) and the channel opening probability (Po) remains unknown. The in vivo significance of this synergism is also not clear. In a mouse model of epilepsy, an increase of SP expression is believed to help induce and maintain Rapamycin in vivo the epileptic status (Liu et al., 1999). Similarly, increases in Src kinase activity are accompanied by the induction of epileptiform activity in rat brain slices and inhibition of Src kinase can reduce epileptiform discharge

(Sanna et al., 2000). Since a reduction in [Ca2+]e is associated with epilepsy, Z-VAD-FMK datasheet and can itself induce epileptiform activity, the synergistic effect of low [Ca2+]e, together with excitatory neuropeptides and/or the activation of Src kinases, on NALCN-mediated currents may provide a powerful excitatory signal to the neurons (Lu et al., 2010). Mutational analyses of Nalcn, Unc79, and Unc80 in mice, D. melanogaster, selleck and C. elegans

have clearly established NALCN as an essential ion channel. Mice without functional Nalcn or Unc79 are neonatal lethal ( Lu et al., 2007, Nakayama et al., 2006 and Speca et al., 2010). In D. melanogaster, and C. elegans, mutating any of the three components of the NALCN complex results in severe behavior phenotypes ( Humphrey et al., 2007, Jospin et al., 2007 and Nash et al., 2002). Perhaps the most common phenotype resulting from mutations in any one of the three NALCN complex components is the disruption in rhythmic behaviors. In mammals, the rhythmic contraction of the diaphragm muscle used for breathing is directly controlled by electrical signals from the nerves. The respiratory rhythms are generated in regions such as the pre-Bötzinger complex (PBC) in the brain stem through network mechanisms and/or together with pacemaking mechanisms (Feldman et al., 2003 and Ramirez et al., 2004). Nalcn mutant mouse pups have severely disrupted respiratory rhythm. Wild-type newborn pups have a rhythmic breathing at a frequency of about one breath per second. In the Nalcn mutant, the breathing is characterized by 5 s of apnea followed by 5 s of breath. This disrupted breathing rhythm represents an “electrical defect,” as the rhythmic electrical discharges recorded from wild-type C4 nerves are essentially absent in the Nalcn mutant ( Lu et al.