Contribution of heteromerization to G protein-coupled receptor function

Abstract

G protein-coupled receptors (GPCRs) are a remarkably multifaceted family of transmembrane proteins that exert a variety of physiological effects. Although family A GPCRs are able to operate as monomers, there is increasing evidence that heteromerization represents a fundamental aspect of receptor function, trafficking and pharmacology. Most recently, it has been suggested that GPCR heteromers may play a crucial role as new molecular targets of heteromer-selective and bivalent ligands. The current review summarizes key recent developments in these topics.

Figure 1

Schematic diagram of the crosstalk mechanisms between 5-HT_2A and mGlu2 receptors. A, Activation of the 5-HT_2A receptor produces an increase of glutamate release in the frontal cortex. It has been suggested that activation of pre-synaptic mGlu2/3 receptors located at glutamatergic terminals modulates negatively this 5-HT_2A receptor-dependent glutamate release. B, Schizophrenia patients carrying the T/T genotype at the 5-HT_2A receptor SNP rs7330461 showed significantly greater improvement in positive and negative syndrome scale (PANSS) total scores during treatment with the mGlu2/3 receptor agonist pomaglumetad compared to A/A homozygous patients. C, Chronic treatment with atypical antipsychotic drugs, such as clozapine, induces repressive histone modifications at the promoter region of the mGlu2 gene via 5-HT_2A receptor-dependent signaling. D, Gq/11-coupled 5-HT2A and Gi/o-coupled mGlu2 receptors form a specific GPCR heteromeric complex though which serotonin and glutamate ligands modulate the pattern of G protein coupling in a way that predicts their psychoactive behavioral effects.