Since this effect affects both NaVs and the “opposing” KVs, the net effects on neuronal excitability due to charge-screening of Ca2+ can be complex. Second, a reduction in [Ca2+]e may influence ion channel selectivity, as best illustrated for CaV. CaVs are highly selective for Ca2+ (PCa/PNa > 1,000), but become nonselective and conduct monovalent ions such as Na+ and K+ when [Ca2+]e is dropped to μM range (Almers and McCleskey, 1984, Hess et al., 1986 and Yang et al., 1993). As the IC50 for the Ca2+-mediated blockade of monovalent ion in CaV’s is ∼1 μM (for CaV1.2), the effect of [Ca2+]e selleck compound on the CaV pore is unlikely

to be responsible for the influence of submillimolar Ca2+e on neuronal excitability. Ca2+e also affects other channels that may be present AZD5363 datasheet in the neuronal membrane, such as the transient receptor potential (TRP) channel family (Owsianik et al., 2006 and Wei et al., 2007). A moderate reduction in [Ca2+]e, to submillimolar levels, for example, can also depolarize some types of neurons. This excitation is unlikely to be explained by the charge screening effect because it is present even when the extracellular divalent cation concentration is kept constant.

One potential mechanism may be via the activation of depolarizing, nonselective cation currents by lowering [Ca2+]e, as found in several types of neurons (Formenti et al., 2001, Hablitz et al., 1986, Smith et al., 2004 and Xiong et al., 1997). The molecular identities of the channels responsible for these currents, the mechanisms by which [Ca2+]e change is coupled

to channel opening, and the role of these channels in the regulation of neuronal excitability by [Ca2+]e remain largely unknown. Recent findings suggest that Ca2+e tightly controls the size of the basal Na+ leak current, IL-Na (Lu et al., 2010). In cultured mouse hippocampal neurons, IL-Na is highly sensitive to [Ca2+]e at the physiological range. Decreasing [Ca2+]e, with [Mg2+]e kept constant, increases IL-Na, with an apparent IC50 of ∼0.1 mM. For example, IL-Na increases from ∼10 pA at a normal [Ca2+]e of 1.5 mM to ∼100 pA when [Ca2+]e Non-specific serine/threonine protein kinase is lowered to 10 μM. Several findings suggest that this increase in IL-Na occurs by an increase of current through NALCN channels (INALCN). First, both the low [Ca2+]e-induced current (ILCa) and INALCN are blocked by 10 μM Gd3+. Second, both currents have a linear I/V relationship passing through 0 mV. Third, ILCa is missing in Nalcn knockout neurons and can be restored upon transfection with NALCN cDNA. Finally, Nalcn knockout hippocampal neurons are not excited when [Ca2+]e is reduced to 10 μM, suggesting that NALCN is the major mechanism by which [Ca2+]e at this range controls neuronal excitability ( Lu et al., 2010). Under other conditions such as further reductions in [Ca2+]e and [Mg2+]e, neuronal excitation can perhaps be mainly achieved via the charge screening effects and/or through the actions of CaVs and TRP channels.