Therefore, the function of UNC79 in mammalian brain may perhaps be to control the stability and trafficking of UNC80, and to determine the localization of the NALCN complex with its various isoforms, thereby indirectly affecting NALCN’s function in various neuronal compartments. In mice and humans, NALCN is expressed in the brain, spinal cord, heart, and pancreas, with the highest mRNA expression levels detected in the brain. In the brain and spinal cord, see more NALCN mRNA is widely expressed, and found in essentially all the neurons (Lu et al., 2007). The expression pattern in the nervous system suggests some fundamental

roles for NALCN, and three basic cellular functions are discussed here. The basal Na+ leak current (IL-Na) is small in most neurons, representing about 10-20 pA of whole cell current at −70 mV

in cultured mouse hippocampal neurons (Lu et al., 2007). Because of its small size, IL-Na is perhaps best measured as the change of holding currents when extracellular Na+ concentration ([Na+]e) is lowered from high (140 mM) to low (14 mM) concentrations under voltage clamping (Raman and Bean, 1997). In the cultured mouse hippocampal neurons, IL-Na can be partially blocked by TTX (∼18%, presumably contributed by the window current through NaV) and by 2 mM Cs (∼10%, likely through HCN channels). The remaining BYL719 in vivo ∼72% current can be almost completely blocked by genetic deletion of Nalcn

or by applying the non-specific NALCN blocker, Gd3+ (10 μM) ( Lu et al., either 2007). The complete elimination of IL-Na by blocking NaVs, HCNs, and NALCN suggests that, in these neurons, these three channels make the major contributions to the resting Na+ leak current, with NALCN having the largest (∼70%) contribution. This is somewhat surprising given that some of the 26 mammalian TRP channels are also found in neurons and, when expressed heterologously, they are open at RMPs ( Ramsey et al., 2006). Many of the TRP channels are used for sensory detection and it’s not clear whether they contribute basal Na+ conductance. The RMP of the Nalcn knockout hippocampal neurons is approximately 10 mV more hyperpolarized than that of wild-type neurons, and is less sensitive to change in [Na+]e. Conversely, overexpression of NALCN leads to a depolarization of ∼20 mV of the RMP ( Lu et al., 2007). In the snail Lymnaea stagnalis, knocking down NALCN in a pacemaker neuron (RPeD1) also leads to an ∼15 mV hyperpolarization of the RMP ( Lu and Feng, 2011). These studies suggest that NALCN is a major player in determining the influence of extracellular Na+ on a neuron’s basal excitability. Like Na+ and K+, extracellular Ca2+ also influences the basal neuronal excitability in many brain regions. The systemic [Ca2+] of the body (∼1.