α6-Containing Nicotinic Acetylcholine Receptor Reconstitution Involves Mechanistically Distinct Accessory Components
| Autor: | Weston B. Davini, G. Brent Dawe, Jose A. Matta, Shenyan Gu, David S. Bredt, Brian Lord |
|---|---|
| Rok vydání: | 2019 |
| Předmět: |
0301 basic medicine
Receptors Nicotinic Synaptic Transmission Nucleus Accumbens General Biochemistry Genetics and Molecular Biology Mice 03 medical and health sciences chemistry.chemical_compound 0302 clinical medicine Dopamine medicine Animals Organic Chemicals Receptor Neurotransmitter Mice Knockout Membrane Glycoproteins biology Lysosome-Associated Membrane Glycoproteins Acetylcholine Corpus Striatum Rats Cell biology Nicotinic acetylcholine receptor 030104 developmental biology Nicotinic agonist chemistry Membrane protein Chaperone (protein) biology.protein Protein Multimerization 030217 neurology & neurosurgery medicine.drug |
| Zdroj: | Cell Reports. 26:866-874.e3 |
| ISSN: | 2211-1247 |
| DOI: | 10.1016/j.celrep.2018.12.103 |
| Popis: | Acetylcholine gates a large family of nicotinic receptor cation channels that control neuronal excitation and neurotransmitter release. These receptors are key targets for neuropsychiatric disorders; however, difficulties in expressing nicotinic acetylcholine (nACh) receptors hamper elaboration of their pharmacology and obscure elucidation of their biological functions. Particularly intriguing are α6-containing nACh receptors, which mediate nicotine-induced dopamine release in striatum-nucleus accumbens. Using genome-wide cDNA screening, we identify three accessory proteins, β-anchoring and -regulatory protein (BARP), lysosomal-associated membrane protein 5 (LAMP5), and SULT2B1, that complement the nACh receptor chaperone NACHO to reconstitute α6β2β3 channel function. Whereas NACHO mediates α6β2β3 assembly, BARP primarily enhances channel gating and LAMP5 and SULT2B1 promote receptor surface trafficking. BARP knockout mice show perturbations in presynaptic striatal nACh receptors that are consistent with BARP modulation of receptor desensitization. These studies unravel the molecular complexity of α6β2β3 biogenesis and enable physiological studies of this crucial neuropharmacological target. |
| Databáze: | OpenAIRE |
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