The existence of basal Na+ conductance was first reported more than 60 years ago. In the squid giant axon, Hodgkin and Katz estimated that the resting relative permeability of Na+ and K+ (PNa/PK) was 0.04 (4%) (Hodgkin and Katz, 1949b). Several cellular mechanisms contribute to the resting background Na+ conductance. First, Na+-dependent cotransporters and some of the electrogenic exchangers allow Na+ into neurons. Second, in some neurons, the hyperpolarization-activated cation channels (HCN, If/Ih current), which conduct Na+, are open at rest

(Robinson and Siegelbaum, 2003). HCN channels are not present in some animals, such as the nematode C. elegans. Third, persistent Na+ currents (INaP) at RMPs can be generated by voltage-gated Na+ (NaV) channels through the “window” current, or by non-inactivating ion channels ( Crill, 1996). The LY2109761 solubility dmso generation of INaP through NaVs is influenced by the voltage-dependence of the channel’s activation and inactivation, which can also be regulated by modulators such as G protein βγ subunits ( Ma et al., 1997). During interspike intervals, NaVs in some neurons can also generate “resurgent” current upon

repolarization because of channel’s recovery from inactivation/block during depolarization ( Grieco et al., 2005 and Raman and Bean, 1997). These subthreshold, NaV-dependent conductances are highly sensitive to voltage and are mostly blocked Ibrutinib by tetrodotoxin (TTX) Suplatast tosilate in the central

nervous system. Finally, many neurons also exhibit a TTX-resistant, voltage-independent, “true” background Na+ conductance (Na+ leak current, IL-Na) ( Atherton and Bevan, 2005, Eggermann et al., 2003, Jackson et al., 2004, Jones, 1989, Khaliq and Bean, 2010, LeSauter et al., 2011, Peña and Ramirez, 2004, Raman et al., 2000 and Russo et al., 2007). The most obvious function of the tonically active background Na+ conductance is perhaps to balance the K+ leak to set the RMP, which would be at ∼−90 mV (EK) in all the neurons if there were only basal K+ conductance. A tonic leak of other ions such as Ca2+, Mg2+, and H+ can hypothetically achieve the same goal, but excessive leak of these ions into neurons can be damaging to the cells because of the cellular metabolism’s high sensitivity to the intracellular concentrations of the ions. By varying the basal PNa/PK, the nervous system can have a wide range of RMPs among different neurons, a heterogeneity in neuronal intrinsic properties known to exist in the brain (Kandel et al., 2000 and Llinás, 1988). Another function of the Na+ conductance is to provide a regulation of the membrane potential by environmental stimuli. One such example was demonstrated in the excitation of sympathetic ganglion neurons in the frog (Jan and Jan, 1982 and Kuffler and Sejnowski, 1983).