Homer1a-Dependent Crosstalk Between NMDA and Metabotropic Glutamate Receptors in Mouse Neurons
MetadataShow full item record
Background: A large number of evidences suggest that group-I metabotropic glutamate receptors (mGluR1a, 1b, 1c, 5a, 5b) can modulate NMDA receptor activity. Interestingly, a physical link exists between these receptors through a Homer-Shank multi-protein scaffold that can be disrupted by the immediate early gene, Homer1a. Whether such a versatile link supports functional crosstalk between the receptors is unknown.
Methodology/Principal Findings: Here we used biochemical, electrophysiological and molecular biological approaches in cultured mouse cerebellar neurons to investigate this issue. We found that Homer1a or dominant negative Shank3 mutants that disrupt the physical link between the receptors allow inhibition of NMDA current by group-I mGluR agonist. This effect is antagonized by pertussis toxin, but not thapsigargin, suggesting the involvement of a G protein, but not intracellular calcium stores. Also, this effect is voltage-sensitive, being present at negative, but not positive membrane potentials. In the presence of DHPG, an apparent NMDA â tail currentâ was evoked by large pulse depolarization, only in neurons transfected with Homer1a. Co-immunoprecipitation experiments showed interaction between G-protein bc subunits and NMDA receptor in the presence of Homer1a and group-I mGluR agonist.
Conclusions/Significance: Altogether these results suggest a direct inhibition of NMDA receptor-channel by Gbetagamma subunits, following disruption of the Homer-Shank3 complex by the immediate early gene Homer1a. This study provides a new molecular mechanism by which group-I mGluRs could dynamically regulate NMDA receptor function.
CitationPLoS One. 2010 Mar 18; 5(3):e9755
- Homer proteins regulate coupling of group I metabotropic glutamate receptors to N-type calcium and M-type potassium channels.
- Authors: Kammermeier PJ, Xiao B, Tu JC, Worley PF, Ikeda SR
- Issue date: 2000 Oct 1
- Dendritic and axonal targeting of type 5 metabotropic glutamate receptor is regulated by homer1 proteins and neuronal excitation.
- Authors: Ango F, Pin JP, Tu JC, Xiao B, Worley PF, Bockaert J, Fagni L
- Issue date: 2000 Dec 1
- Homer 1a uncouples metabotropic glutamate receptor 5 from postsynaptic effectors.
- Authors: Kammermeier PJ, Worley PF
- Issue date: 2007 Apr 3
- Scaffolding protein Homer1a protects against NMDA-induced neuronal injury.
- Authors: Wang Y, Rao W, Zhang C, Zhang C, Liu MD, Han F, Yao LB, Han H, Luo P, Su N, Fei Z
- Issue date: 2015 Aug 6
- Agonist-independent activation of metabotropic glutamate receptors by the intracellular protein Homer.
- Authors: Ango F, Prézeau L, Muller T, Tu JC, Xiao B, Worley PF, Pin JP, Bockaert J, Fagni L
- Issue date: 2001 Jun 21