In this renewal application, we propose to extend our discoveries during the previous funding period on the ion channel protein complex of NALCN, UNC79 and UNC80. We discovered that the NALCN protein forms a complex with UNC79 and UNC80 in mammalian brain and is a major contributor the basal sodium leak conductance in the neurons. The channel is also controlled by neuro-peptides through G protein-coupled receptors but in a G protein-independent fashion. Knocking out Nalcn or Unc79 leads to neonatal lethality and the mutant neurons are less excitable. UNC79 and UNC80 are large novel proteins well conserved among species. They are required for the ion channel function. Despite their large sizes (~3,000 amino acids), they do not have recognizable domains. We will use biochemical and electrophysiological studies to define the interaction domains on each of the proteins, and find out their contribution to the ion channel function (aims 1 and 2). NALCN's G protein-independent activation is quite unique and it provides an opportunity to dissect this unusual ion channel activation pathway by G protein-coupled receptors.
In aim 3, we study the mechanisms of this activation by revealing the protein domains and the signaling steps important for the pathway. Results from these studies will help us understand how neuronal excitability is regulated at the molecular level under physiological and pathophysiological conditions such as autism, paralysis, seizure and epilepsy.

Public Health Relevance

This renewal proposal studies how the excitability of neurons is regulated by a sodium leak ion channel protein complex. Results from these studies will help understand neuronal excitabilities in physiological and pathophysiological conditions such as autism, paralysis, seizure and epilepsy

National Institute of Health (NIH)
National Institute of Neurological Disorders and Stroke (NINDS)
Research Project (R01)
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Neurotransporters, Receptors, and Calcium Signaling Study Section (NTRC)
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Stewart, Randall R
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University of Pennsylvania
Schools of Arts and Sciences
United States
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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

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