, 2005 and Nash et al., 2002). Consistent with this prediction, the pacemaker neurons in the mutant have higher level of PDF (pigment-dispersing factor, a neuropeptide released by the pacemaker neurons to coordinate circadian behaviors in the flies),

suggesting a potential decrease in the release of PDF (and/or an increase in production) by these neurons in the mutant ( Lear et al., 2005). Transgenic expression of NA in circadian pacemaker neurons in the na mutant using the Gal4-UAS system restores the circadian phenotypes ( Lear et al., 2005). Remarkably, NA expression in a small subset of the neurons (∼20 DN1 dorsal neurons) is sufficient to rescue some of the phenotypes, including the acute light-on PD0325901 in vitro locomotor activity

response ( Zhang et al., 2010). It is not clear whether any residual function of the NA protein in the hypomorphic mutant learn more used for the rescue experiment, if present, plays a supporting role in the other neurons. How NA contributes the fly circadian responses remains further investigated, but it’s interesting to note that mammalian NALCN is activated by neuropeptides in hippocampal, VTA and pre-Bötzinger complex pacemaking neurons ( Lu et al., 2009, Peña and Ramirez, 2004 and Ptak et al., 2009), and the channel appears to be controlled by light input in the SCN ( LeSauter et al., 2011). In autonomously firing neurons and pacemaking neurons within a local circuitry, NALCN as a channel that leaks Na+-mediated current may provide a constant, noninactivating, depolarizing force used to generate or modulate the rhythmic electrical activities for the control of behaviors (Atherton and Bevan, 2005, Jackson et al., 2004, Khaliq and Bean, 2010, Ptak et al., 2009, Raman et al., 2000 and Russo et al., 2007). Oscillation of membrane potential is not restricted to neurons in the brain and spinal cord but rather can be found throughout the body and is perhaps best characterized

in the SA node and conduction system cells of heart. The depolarizing force during the diastole cycle in the heart is a result of interplay of several ion channels, but HCNs (Ih) are generally believed to be the major contributor (DiFrancesco, 2006 and Vassalle, 1995). However, HCN knockout adult mice have roughly normal Chlormezanone (Herrmann et al., 2007) or reduced heartbeat rates (Baruscotti et al., 2011), and the rate acceleration by sympathetic stimulation is intact, suggesting additional important player in heart rate regulation. NALCN is also highly expressed in the heart (Lee et al., 1999). The use of conditional Nalcn knockout mice should clarify whether NALCN plays a role in heartbeat control. Likewise, NALCN is expressed in pancreatic β cells, where the rhythmic oscillation of Em is coupled to cell glucose metabolism and the secretion of insulin.