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

Agency
National Institute of Health (NIH)
Type
Research Project (R01)
Project #
5R01NS055293-07
Application #
8738717
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
7
Fiscal Year
2014
Total Cost
Indirect Cost
Name
University of Pennsylvania
Department
Biology
Type
Schools of Arts and Sciences
DUNS #
City
Philadelphia
State
PA
Country
United States
Zip Code
19104
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
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
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; Bekele, Biruk; Ren, Dejian (2014) The voltage-gated sodium channel TPC1 confers endolysosomal excitability. Nat Chem Biol 10:463-9
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; Zhou, Yandong; Navarro, Betsy et al. (2013) mTOR regulates lysosomal ATP-sensitive two-pore Na(+) channels to adapt to metabolic state. Cell 152:778-90
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
Wang, Xiang; Zhang, Xiaoli; Dong, Xian-Ping et al. (2012) TPC proteins are phosphoinositide- activated sodium-selective ion channels in endosomes and lysosomes. Cell 151:372-83
Ren, Dejian (2011) Sodium leak channels in neuronal excitability and rhythmic behaviors. Neuron 72:899-911

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