Lynx in organization and dynamics of nicotinic acetylcholine receptor complexes Channelopathies are diseases of ion channel dysfunction, arising either in channel proteins themselves or in associated proteins. They can arise either genetically or via autoimmune reaction. Mis-regulation of nicotinic acetylcholine receptors (nAChRs) is linked to neural disorders, including schizophrenia, some epilepsies, nicotine addiction, myasthenia gravis, Alzheimer's disease, and Parkinson's disease. Common findings are that the number and localization of nAChRs are altered during in the disease state, and that restoration of their correct number and distribution can ameliorate disease phenotypes. Localization in synaptic vs extrasynaptic areas is also a crucial aspect of nAChR function. Lynx proteins are widely expressed regulators of nicotinic receptor function. Removal of the lynx1 gene results in nAChR hypersensitivity, enhanced learning, and extended critical periods for binocular selectivity, but also susceptibility to neurodegeneration. Genetic, biochemical, and physiological studies indicate direct or indirect interactions between 17 and 1422 nAChRs. Lynx proteins have (a) GPI anchors and (b) structural and functional similarities to the soluble nAChR ligands, 1-bungarotoxin and related toxins from snakes and snails. GPI-anchored membrane proteins can influence the distribution and mobility of surface receptors, through their preferential association with well-ordered, cholesterol-rich domains and nanodomains that accumulate signaling molecules and cytoskeletal components at the plasma membrane. These molecular events can produce an altered microenvironment, influencing receptor distribution and lifetime at the cell surface. Therefore, this project investigates the effect of lynx-nAChR interactions on the mechanisms of nAChR trafficking to the plasma membrane, the distribution of nAChRs on the plasma membrane, the mechanisms of internalization of surface nAChRs, and the underlying interactions with cytoskeletal and trafficking machinery.

Public Health Relevance

The worldwide health burden of neural disease is projected to increase 5-fold by year 2050, to >$1trillion/year. Optimal therapies do not yet exist for several neural diseases that involve nicotinic receptors: Alzheimer's disease, cognitive dysfunction, schizophrenia, nicotine addiction, some epilepsies, and myasthenia gravis. Nicotinic receptors are also promising targets for therapeutics, for instance in Parkinson's disease and mood disorders.

Agency
National Institute of Health (NIH)
Institute
National Institute on Drug Abuse (NIDA)
Type
Exploratory/Developmental Grants (R21)
Project #
1R21DA033831-01
Application #
8246947
Study Section
Special Emphasis Panel (ZRG1-BDCN-L (52))
Program Officer
Rapaka, Rao
Project Start
2012-04-01
Project End
2013-01-02
Budget Start
2012-04-01
Budget End
2013-01-02
Support Year
1
Fiscal Year
2012
Total Cost
$172,680
Indirect Cost
$68,302
Name
California Institute of Technology
Department
None
Type
Schools of Arts and Sciences
DUNS #
009584210
City
Pasadena
State
CA
Country
United States
Zip Code
91125
Kobayashi, Atsuko; Parker, Rell L; Wright, Ashley P et al. (2014) Lynx1 supports neuronal health in the mouse dorsal striatum during aging: an ultrastructural investigation. J Mol Neurosci 53:525-36
Nichols, Weston A; Henderson, Brandon J; Yu, Caroline et al. (2014) Lynx1 shifts ?4?2 nicotinic receptor subunit stoichiometry by affecting assembly in the endoplasmic reticulum. J Biol Chem 289:31423-32