The major goal of this proposal is to build on our several recent unexpected findings to understand how extracellular calcium regulates the basal excitability of neurons. Under pathophysiological conditions such as hypocalcemia and epilepsy, concentration of extracellular calcium can drop significantly in the brain. Extracellular calcium concentration can also change under physiological conditions in brain regions with high neuronal density and in microdomains such as the synaptic cleft. A decrease in extracellular calcium concentration usually excites neurons. The molecular mechanisms underlying the control by extracellular calcium are poorly understood, in contrast with the extensively investigated intracellular roles of calcium as a second messenger. We propose that a major mechanism by which extracellular calcium regulates excitability is through the NALCN cation channel we discovered. Using biochemical, electrophysiology and mouse genetics approaches, we will 1) determine the relative contribution of NALCN to the neuronal excitation by extracellular calcium in several brain regions; 2) define the structural requirements of the protein in the calcium sensitivity; and 3) uncover the signals that regulate the channel complex. Results from these studies will help us understand how body calcium regulates neuronal excitability at the molecular level under physiological and pathophysiological conditions such as paralysis, seizure and epilepsy.

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This proposal studies how extracellular calcium controls the excitability of the nervous system. Results from these studies will help understand 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)
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Neurotransporters, Receptors, and Calcium Signaling Study Section (NTRC)
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Silberberg, Shai D
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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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