Functional Roles of Na+ Leak Channels and Na+-Ca2+ Exchangers in Clock Neurons of the Rat Suprachiasmatic Nucleus

The circadian firing activity of hypothalamic suprachiasmatic nucleus (SCN) clock neurons allows them to control the circadian rhythms in mammals. These clock neurons convey day-night information by altering their spontaneous firing rate in a circadian manner, higher at day and lower at night. The ionic mechanisms for circadian firing, however, remain poorly understood. They also exhibit metabolic rhythms, with higher daytime glucose uptake, Na/K pump activity, and intracellular Ca2+ levels. The higher daytime firing and Na/K pump activity and glucose uptake in SCN neurons may suggest that the parallel increase in Na/K pump activity, and thus in glucose utilization to fuel the energy-demanding process, is to meet the demand of increased Na+ loading associated with higher daytime firing rate. Nonetheless, our unpublished results indicate that the energy-demanding Na+ extrusion is not activated by the opening of TTX-sensitive Na+ channels, but by a divalent cation-sensitive Na+ leak channel functionally coupled to the Na/K pump. As active extrusion of Na+ is energy demanding, the coupling between Na+ leak channels and Na/K pumps indicates a necessary presence and thus functional importance of Na+ leak channels in SCN neurons. Most likely these channels carry inward currents to maintain relatively depolarized resting potentials to help drive spontaneous firing in the clock neurons. However, the nature of the proposed divalent cation-sensitive Na+ leak channel remained to be determined. As the pump current is larger at day than at night, the coupling also suggests a larger Na+ leak current during the day, thus accounting for the higher daytime firing rate. This is an interesting and potentially important prediction awaiting experimental confirmation. On the other hand, the coupling also suggest that Na+ leak channels and Na/K pumps interact to regulate [Na+]i, which may then act on Na+–Ca2+ exchanger (NCX) to regulate intracellular Ca2+ homeostasis. Apart from playing a major role in Ca2+ regulation, the electrogenic nature of NCX also suggests a role in the regulation of cell excitability. This three years project aims to investigate the Na+ leak channel, the NCX, and the regulation of NCX by Na+ leak channels and Na/K pumps. In the first year we will determine the ionic mechanism for the proposed Na+ leak channel and investigate its role in SCN neuronal excitability, most importantly, the predicted daily rhythm of channel activity. In the second year we will study the functional role of NCX in the regulation of SCN neuronal excitability. In the third year, we will determine the role of Na+ leak channels and Na/K pump in the regulation of NCX to control Ca2+ homeostasis and neuronal excitability.

Project ID:PC10101-2041
External Project ID:NSC100-2320-B182-009-MY3