Modulation of 5-HT3 receptor desensitization by the light chain of microtubule-associated protein 1B expressed in HEK 293 cells |
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Authors: | Sun Hui Hu Xiang-Qun Emerit Michel B Schoenebeck Jeffrey C Kimmel Cassin E Peoples Robert W Miko Angela Zhang Li |
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Affiliation: | Laboratory for Integrative Neuroscience, National Institute on Alcohol Abuse and Alcoholism, National Institutes of Health, 5625 Fishers Lane, Bethesda, MD 20892, USA;INSERM U677, Neuropsychopharmacologie Moléculaire, Cellulaire et Fonctionelle, C.H.U. Pitié-Salpêtrière, 91 Bd de l'Hôpital, 75634 Paris Cedex 13, France;Department of Biomedical Sciences, College of Health Sciences, Marquette University, Milwaukee, WI 53201-1881, USA |
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Abstract: | Regulation of ligand-gated ion channel (LGIC) function and trafficking by cytoskeleton proteins has been the topic of recent research. Here, we report that the light chain (LC1) of microtubule-associated protein 1B (MAP1B) specifically interacted with the 5-HT3A receptor, a predominant serotonin-gated ion channel in the brain. LC1 and 5-HT3A receptors were colocalized in central neurons and in HEK 293 cells expressing 5-HT3A receptors. LC1 reduced the steady-state density of 5-HT3A receptors at the membrane surface of HEK 293 cells and significantly accelerated receptor desensitization time constants from 3.8 ± 0.3 s to 0.8 ± 0.1 s. However, LC1 did not significantly alter agonist binding affinity and single-channel conductance of 5-HT3A receptors. On the other hand, application of specific LC1 antisense oligonucleotides and nocodazole, a microtubule disruptor, significantly prolonged the desensitization time of the recombinant and native neuronal 5-HT3 receptors by 3- to 6-fold. This kinetic change induced by nocodazole was completely rescued by addition of LC1 but not GABAA receptor-associated protein (GABARAP), suggesting that LC1 can specifically interact with 5-HT3A receptors. These observations suggest that the LC1–5-HT3A receptor interaction contributes to a mechanism that regulates receptor desensitization kinetics. Such dynamic regulation may play a role in reshaping the efficacy of 5-HT3 receptor-mediated synaptic transmission. |
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