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.

National Institute of Health (NIH)
National Institute of Neurological Disorders and Stroke (NINDS)
Research Project (R01)
Project #
Application #
Study Section
Neurotransporters, Receptors, and Calcium Signaling Study Section (NTRC)
Program Officer
Stewart, Randall R
Project Start
Project End
Budget Start
Budget End
Support Year
Fiscal Year
Total Cost
Indirect Cost
University of Pennsylvania
Schools of Arts and Sciences
United States
Zip Code
Hirschi, Marscha; Herzik Jr, Mark A; Wie, Jinhong et al. (2017) Cryo-electron microscopy structure of the lysosomal calcium-permeable channel TRPML3. Nature 550:411-414
Yeh, Szu-Ying; Huang, Wei-Hsiang; Wang, Wei et al. (2017) Respiratory Network Stability and Modulatory Response to Substance P Require Nalcn. Neuron 94:294-303.e4
Lee, Changkeun; Guo, Jiangtao; Zeng, Weizhong et al. (2017) The lysosomal potassium channel TMEM175 adopts a novel tetrameric architecture. Nature 547:472-475
Guo, Jiangtao; Zeng, Weizhong; Chen, Qingfeng et al. (2016) Structure of the voltage-gated two-pore channel TPC1 from Arabidopsis thaliana. Nature 531:196-201
Stray-Pedersen, Asbjørg; Cobben, Jan-Maarten; Prescott, Trine E et al. (2016) Biallelic Mutations in UNC80 Cause Persistent Hypotonia, Encephalopathy, Growth Retardation, and Severe Intellectual Disability. Am J Hum Genet 98:202-9
Flourakis, Matthieu; Kula-Eversole, Elzbieta; Hutchison, Alan L et al. (2015) A Conserved Bicycle Model for Circadian Clock Control of Membrane Excitability. Cell 162:836-48
Xu, Haoxing; Ren, Dejian (2015) Lysosomal physiology. Annu Rev Physiol 77:57-80
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
Cang, Chunlei; Zhou, Yandong; Navarro, Betsy et al. (2013) mTOR regulates lysosomal ATP-sensitive two-pore Na(+) channels to adapt to metabolic state. Cell 152:778-790

Showing the most recent 10 out of 16 publications