title: β-Arrestin-Dependent Dopaminergic Regulation of Calcium Channel Activity in the Axon Initial Segment.
abstract: G-protein-coupled receptors (GPCRs) initiate a variety of signaling cascades, depending on effector coupling. β-arrestins, which were initially characterized by their ability to "arrest" GPCR signaling by uncoupling receptor and G protein, have recently emerged as important signaling effectors for GPCRs. β-arrestins engage signaling pathways that are distinct from those mediated by G protein. As such, arrestin-dependent signaling can play a unique role in regulating cell function, but whether neuromodulatory GPCRs utilize β-arrestin-dependent signaling to regulate neuronal excitability remains unclear. Here, we find that D3 dopamine receptors (D3R) regulate axon initial segment (AIS) excitability through β-arrestin-dependent signaling, modifying CaV3 voltage dependence to suppress high-frequency action potential generation. This non-canonical D3R signaling thereby gates AIS excitability via pathways distinct from classical GPCR signaling pathways.
authors.affiliation: Center for Integrative Neuroscience, University of California, San Francisco, San Francisco, CA 94158, USA; Alcohol and Addiction Research Group, Department of Neurology, University of California, San Francisco, San Francisco, CA 94158, USA.
authors.forename: Sungchil
authors.initials: S
authors.lastname: Yang
authors.affiliation: Center for Integrative Neuroscience, University of California, San Francisco, San Francisco, CA 94158, USA; Alcohol and Addiction Research Group, Department of Neurology, University of California, San Francisco, San Francisco, CA 94158, USA.
authors.forename: Roy
authors.initials: R
authors.lastname: Ben-Shalom
authors.affiliation: Department of Pathology and Institute for Neurodegenerative Diseases, University of California, San Francisco, San Francisco, CA 94158, USA.
authors.forename: Misol
authors.initials: M
authors.lastname: Ahn
authors.affiliation: Center for Integrative Neuroscience, University of California, San Francisco, San Francisco, CA 94158, USA; Alcohol and Addiction Research Group, Department of Neurology, University of California, San Francisco, San Francisco, CA 94158, USA.
authors.forename: Alayna T
authors.initials: AT
authors.lastname: Liptak
authors.affiliation: Department of Medicinal Chemistry and Molecular Pharmacology, Purdue University, West Lafayette, IN 47907, USA.
authors.forename: Richard M
authors.initials: RM
authors.lastname: van Rijn
authors.affiliation: Alcohol and Addiction Research Group, Department of Neurology, University of California, San Francisco, San Francisco, CA 94158, USA.
authors.forename: Jennifer L
authors.initials: JL
authors.lastname: Whistler
authors.affiliation: Center for Integrative Neuroscience, University of California, San Francisco, San Francisco, CA 94158, USA; Alcohol and Addiction Research Group, Department of Neurology, University of California, San Francisco, San Francisco, CA 94158, USA. Electronic address: kevin.bender@ucsf.edu.
authors.forename: Kevin J
authors.initials: KJ
authors.lastname: Bender
mesh_terms: D000818:Animals; D000071040:Axon Initial Segment / Q000378:metabolism*; D002118:Calcium / Q000378:metabolism; D015220:Calcium Channels / Q000378:metabolism*; D004298:Dopamine / Q000378:metabolism*; D057809:HEK293 Cells; D006801:Humans; D010766:Phosphorylation; D043562:Receptors, G-Protein-Coupled / Q000378:metabolism; D000071557:beta-Arrestins / Q000378:metabolism*
chemical_list: D015220:Calcium Channels; D043562:Receptors, G-Protein-Coupled; D000071557:beta-Arrestins; D002118:Calcium; D004298:Dopamine