This proposal focuses on a sodium leak channel (NALCN) and its regulation by neurotransmitters in the nervous systems. NALCN ion channel belongs to the family that also includes the ten voltage-gated calcium channels and ten sodium channels. However, the NALCN channel is non-selective (permeable to sodium, calcium and potassium), and the channel's activation is voltage-independent. In the mutant mice deficient in the channel gene, there is defect in breathing rhythm and the mutant animals do not survive beyond 24 hours of birth. Thus, NALCN is one of the few ion channels indispensable for animal's survival. The mutant hippocampal neurons lack the cesium and TTX-insensitive sodium leak current and the neurons'membrane potential is little sensitive to changes in extracellular sodium concentrations. Using Northern blot and in situ hybridization, aim 1 will localize the gene expression in the animal.
Aim 2 will determine the molecular mechanisms underlying NALCN's unique ion selectivity.
Aim 3 will use patch clamp to compare the excitabilities of the wild-type and the mutant neurons and determine the contribution of NALCN channel to neuronal excitability.
Aim 4 will examine how the NALCN channel is regulated by neurotransmitters. Results from these studies will reveal the physiological roles of this vital gene. They may also reveal how the function of the protein can influence neuronal excitabilities in physiological and pathophysiological conditions such as paralysis, seizure and epilepsy.
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