The ability of seven transmembrane receptors (7TM receptors) to interact with a diverse set of protein partners in a rapid and kinetically favorable way could result from an effective compartmentalization of the receptor/protein components in the plasma membrane microdomains. One such microdomain may be lipid rafts and their subdomain caveolae that were recently proposed to have an important role in efficient signaling and receptor-protein partner interactions. We therefore examined the impact of lipid raft/caveolae microdomains on receptor micro-localization within the plasma membrane, the receptor-protein partner interactions and receptor signaling properties. For the purpose of the study neurokinin type 1 receptor (NK1-R) was stably expressed in chinese hamster ovary (CHO) cell lines, CHO K₁ and mutant CHO 215 that have a defect in the synthesis of cholesterol and consequently the formation of lipid rafts in those cells is inhibited. We employed electron paramagnetic resonance (EPR) with spin labeling to study the domain structure of the plasma membrane and receptor microlocalization. A fitting procedure called GHOST was utilized that provides a means for quantitative characterization of complex bio-membrane systems. We showed that NK1-R was distributed in a well-ordered domain of the CHO-K₁ representing lipid raft/caveolae microdomains, whereas in CHO-215 cells lacking lipid rafts/caveolae the NK1-R plasma-membrane distribution was impaired. We then assessed receptor signaling properties and employed bioluminescence resonance energy transfer (BRET²) to obtain data of relevance for receptor/beta-arrestins interactions. Our results showed that receptor compartmentalization within the plasma membrane caveolae/lipid rafts microdomains influence the efficacy of receptor signaling as well as agonist-induced receptor/beta-arrestin 2 interactions resulting in a decreased desensitization. In this aspect, our findings could provide a new framework to study the functional importance of caveolae/lipid rafts in the context of 7TM receptors and their interacting protein partners.