Unraveling the functions of endogenous receptor oligomers in the brain using interfering peptide: The example of D1R/NMDAR heteromers

Decoding signaling pathways in different brain structures is crucial to develop pharmacological strategies for neurological diseases. In this perspective, the targeting of receptors by selective ligands is one of the classical therapeutic strategies. Nonetheless, this approach often results in a decrease of efficiency over time and deleterious side effects because physiological functions can be affected. An emerging concept has been to target mechanisms that fine-tune receptor signaling, such as heteromerization, the process by which physical receptor–receptor interaction at the membrane allows the reciprocal modulation of receptors’ signaling. Because of the central role of the synergistic transmission mediated by dopamine (DA) and glutamate (Glu) in brain physiology and pathophysiology, heteromerization between DA and Glu receptors has received a lot of attention. However, the study of endogenous heteromers has been challenging because of the lack of appropriate tools. Over the last years, progress has been made in the development of techniques to study their expression in the brain, regulation and function. In this chapter, we provide a methodological framework for the design and use of interfering peptides to study endogenous receptor oligomers through the example of the dopamine type 1 receptor (D1R) and the GluN1 subunit of NMDA receptor heteromers.