title: GPCRs promote the release of zinc ions mediated by nNOS/NO and the redox transducer RGSZ2 protein.
abstract: OBJECTIVE
  Morphine signaling via the μ-opioid receptor (MOR) is coupled to redox-dependent zinc release from endogenous stores. Thus, MOR activation stimulates the complex formed by RGSZ2 (a regulator of G protein signaling) and neural nitric oxide synthase (nNOS) to produce NO, and to recruit PKCγ and Raf-1 in a zinc-dependent manner. Accordingly, we investigated whether redox regulation of zinc metabolism was unique to the MOR, or if it is a signaling mechanism shared by G-protein coupled receptors (GPCRs).
  
  
  RESULTS
  A physical interaction with the RGSZ2-nNOS complex was detected for the following GPCRs: neuropeptides, MOR and δ-opioid (DOR); biogenic amines, 5HT1A, 5HT2A, α2A, D1 and D2; acetylcholine, muscarinic M2 and M4; excitatory amino acid glutamate, mGlu2 and mGlu5; and derivatives of arachidonic acid (anandamide), CB1. Agonist activation of these receptors induced the release of zinc ions from the RGSZ2 zinc finger via a nNOS/NO-dependent mechanism, recruiting PKCγ and Raf-1 to the C terminus or the third internal loop of the GPCR.
  
  
  METHODS
  A series of GPCRs share an unexpected mechanistic feature, the nNOS/NO-dependent regulation of zinc ion signaling via a redox mechanism. The RGSZ2 protein emerges as a potential redox zinc switch that converts NO signals into zinc signals, thereby able to modulate the function of redox sensor proteins like PKCγ or Raf-1.
  
  
  CONCLUSIONS
  Redox mechanisms are crucial for the successful propagation of GPCR signals in neurons. Thus, dysfunctions of GPCR-regulated NO/zinc signaling may contribute to neurodegenerative and mood disorders such as Alzheimer's disease and depression.
authors.affiliation: Cajal Institute, Consejo Superior de Investigaciones Científicas, Madrid, Spain.
authors.forename: Pilar
authors.initials: P
authors.lastname: Sánchez-Blázquez
authors.forename: María
authors.initials: M
authors.lastname: Rodríguez-Muñoz
authors.forename: Concha
authors.initials: C
authors.lastname: Bailón
authors.forename: Javier
authors.initials: J
authors.lastname: Garzón
mesh_terms: D000818:Animals; D047468:Immunoprecipitation; D051379:Mice; D052248:Nitric Oxide Synthase Type I / Q000378:metabolism*; D009589:Nitrogen Oxides / Q000378:metabolism*; D010084:Oxidation-Reduction; D011485:Protein Binding; D020710:RGS Proteins / Q000378:metabolism*; D043562:Receptors, G-Protein-Coupled / Q000378:metabolism*; D015032:Zinc / Q000378:metabolism*
chemical_list: D009589:Nitrogen Oxides; D020710:RGS Proteins; C532880:RGS17 protein, mouse; D043562:Receptors, G-Protein-Coupled; D052248:Nitric Oxide Synthase Type I; D015032:Zinc