title: Chronic opioid treatment augments caveolin-1 scaffolding: relevance to stimulatory μ-opioid receptor adenylyl cyclase signaling.
abstract: Caveolin-1 is the predominant structural protein of caveolae, a subset of (lipid) membrane rafts that compartmentalize cell signaling. Caveolin-1 binds most to G protein-coupled receptors and their signaling partners, thereby enhancing interactions among signaling cascade components and the relative activation of specific G protein-coupled pathways. This study reveals that chronic opioid exposure of μ-opioid receptor (MOR) expressing Chinese hamster ovary cells (MOR-CHO) and chronic in vivo morphine exposure of rat spinal cord augmented recruitment of multiple components of MOR-adenylyl cyclase (AC) stimulatory signaling by caveolin-1. Strikingly, in MOR-CHO and spinal cord, blocking the caveolin-1 scaffolding domain substantially attenuated the chronic morphine-induced increased interaction of caveolin-1 with MOR, Gsα, protein phosphatase 2A (PP2A), and AC. Chronic morphine treatment also increased interactions among the above signaling proteins, thus enabling sufentanil to stimulate (rather than inhibit) cAMP production within lipid membrane microdomains. The latter finding underscores the functionality of augmented interactions among MOR, Gsα, PP2A, and AC. In the aggregate, our data strongly suggest that augmented caveolin-1 scaffolding undergirds the ability of chronic opioids to recruit an ancillary signaling pathway by acting as an organizing template for MOR-Gsα-AC signaling and delimiting the membrane compartment(s) in which it occurs. Since caveolin-1 binds to a wide spectrum of signaling molecules, altered caveolin-1 scaffolding following chronic opioid treatment is likely to pertain to most, if not all, MOR signaling partners. The chronic morphine-induced trigger that augments caveolin-1 scaffolding could represent a seminal perturbation that initiates the wide spectrum of adaptations thought to contribute to opioid tolerance and dependence.
authors.affiliation: Department of Obstetrics and Gynecology, State University of New York, Downstate Medical Center, Brooklyn, New York, USA.
authors.forename: Sumita
authors.initials: S
authors.lastname: Chakrabarti
authors.affiliation: Department of Obstetrics and Gynecology, State University of New York, Downstate Medical Center, Brooklyn, New York, USA.
authors.forename: Andrew
authors.initials: A
authors.lastname: Chang
authors.affiliation: Department of Obstetrics and Gynecology, State University of New York, Downstate Medical Center, Brooklyn, New York, USA.
authors.forename: Nai-Jiang
authors.initials: NJ
authors.lastname: Liu
authors.affiliation: Department of Obstetrics and Gynecology, State University of New York, Downstate Medical Center, Brooklyn, New York, USA.
authors.forename: Alan R
authors.initials: AR
authors.lastname: Gintzler
mesh_terms: D000262:Adenylyl Cyclases / Q000378:metabolism*; D000701:Analgesics, Opioid / Q000008:administration & dosage*; D000818:Animals; D016466:CHO Cells; D051242:Caveolin 1 / Q000008:administration & dosage*; D006224:Cricetinae; D003412:Cricetulus; D004334:Drug Administration Schedule; D004357:Drug Synergism; D051381:Rats; D017450:Receptors, Opioid, mu / Q000819:agonists* / Q000378:metabolism*
chemical_list: D000701:Analgesics, Opioid; D051242:Caveolin 1; D017450:Receptors, Opioid, mu; D000262:Adenylyl Cyclases
keywords: caveolae; caveolin-1; opioid tolerance; opioids; μ-opioid receptor