Antioxidants & Redox Signaling

GPCRs Promote the Release of Zinc Ions Mediated by nNOS/NO and the Redox Transducer RGSZ2 Protein

To cite this article:
Pilar Sánchez-Blázquez, María Rodríguez-Muñoz, Concha Bailón, and Javier Garzón. Antioxidants & Redox Signaling. -Not available-, ahead of print. doi:10.1089/ars.2012.4517.

Online Ahead of Print: July 10, 2012
Online Ahead of Editing: May 7, 2012

Author information

Pilar Sánchez-Blázquez, María Rodríguez-Muñoz, Concha Bailón, and Javier Garzón

Cajal Institute, Consejo Superior de Investigaciones Científicas, Madrid, Spain.

Address correspondence to:

Prof. Javier Garzón

Instituto Cajal

Consejo Superior de Investigaciones Científicas (CSIC)

Doctor Arce 37, 28002 Madrid

Spain
E-mail: jgarzon@cajal.csic.es

Date of first submission to ARS Central, January 11, 2012
date of final revised submission, May 4, 2012
date of acceptance, May 6, 2012

ABSTRACT

Abstract

Aims: 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. Innovation: 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. Conclusion: 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.

Antioxid. Redox Signal. 00, 000—000.