Coevolution of Residues Provides Evidence of a Functional Heterodimer of 5-HT_2AR and 5-HT_2CR Involving Both Intracellular and Extracellular Domains

Serotonin is a neurotransmitter that plays a role in regulating activities such as sleep, appetite, mood and substance abuse disorders; serotonin receptors 5-HT_2AR and 5-HT_2CR are active within pathways associated with substance abuse. It has been suggested that 5-HT_2AR and 5-HT_2CR may form a dimer that affects behavioral processes. Here we study the coevolution of residues in 5-HT_2AR and 5-HT_2CR to identify potential interactions between residues in both proteins. Coevolution studies can detect protein interactions, and since the thus uncovered interactions are subject to evolutionary pressure, they are likely functional. We assessed the significance of the 5-HT_2AR/5-HT_2CR interactions using randomized phylogenetic trees and found the coevolution significant (p-value = 0.01). We also discuss how co-expression of the receptors suggests the predicted interaction is functional. Finally, we analyze how several single nucleotide polymorphisms for the 5-HT_2AR and 5-HT_2CR genes affect their interaction. Our findings are the first to characterize the binding interface of 5-HT_2AR/5-HT_2CR and indicate a correlation between this interface and location of SNPs in both proteins.