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.

Agency
National Institute of Health (NIH)
Institute
National Institute of Neurological Disorders and Stroke (NINDS)
Type
Research Project (R01)
Project #
5R01NS055293-05
Application #
8206702
Study Section
Neurotransporters, Receptors, and Calcium Signaling Study Section (NTRC)
Program Officer
Stewart, Randall R
Project Start
2008-01-01
Project End
2013-09-29
Budget Start
2012-01-01
Budget End
2013-09-29
Support Year
5
Fiscal Year
2012
Total Cost
$337,641
Indirect Cost
$123,266
Name
University of Pennsylvania
Department
Biology
Type
Schools of Arts and Sciences
DUNS #
042250712
City
Philadelphia
State
PA
Country
United States
Zip Code
19104
Cang, Chunlei; Aranda, Kimberly; Ren, Dejian (2014) A non-inactivating high-voltage-activated two-pore Na? channel that supports ultra-long action potentials and membrane bistability. Nat Commun 5:5015
Cang, Chunlei; Bekele, Biruk; Ren, Dejian (2014) The voltage-gated sodium channel TPC1 confers endolysosomal excitability. Nat Chem Biol 10:463-9
Kim, Byung Joo; Chang, In Youb; Choi, Seok et al. (2012) Involvement of Na(+)-leak channel in substance P-induced depolarization of pacemaking activity in interstitial cells of Cajal. Cell Physiol Biochem 29:501-10
Ren, Dejian (2011) Sodium leak channels in neuronal excitability and rhythmic behaviors. Neuron 72:899-911
Lu, Boxun; Zhang, Qi; Wang, Haikun et al. (2010) Extracellular calcium controls background current and neuronal excitability via an UNC79-UNC80-NALCN cation channel complex. Neuron 68:488-99
Wang, Haikun; Ren, Dejian (2009) UNC80 functions as a scaffold for Src kinases in NALCN channel function. Channels (Austin) 3:161-3
Lu, Boxun; Su, Yanhua; Das, Sudipto et al. (2009) Peptide neurotransmitters activate a cation channel complex of NALCN and UNC-80. Nature 457:741-4