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G protein-coupled receptors (GPCRs) detect and distinguish between various subtypes of extracellular signals, such as neurotransmitters, hormones, light, and odorous chemicals. As determinants for robust and appropriate cellular responses, common and unique features of interactions between GPCRs and their target G proteins provide insights into structure-based drug design for treatment of GPCR-related diseases. Recently, we found that the hydrophobic core buried between GPCR helix 8 and TM1–2 is essential for activation of both specific and nonspecific G proteins. Furthermore, the 2^nd residue of helix 8 is responsible for initial, transient, and specific interaction with a target G protein. Analysis of human and murine olfactory receptors (ORs) and other class-A GPCRs revealed that several amino acids, such as Glu, Gln, and Asp, are conserved at this position. This analysis enabled one sub-classification for 64 of 88 non-olfactory GPCR groups associated with a set of agonists and target G protein subtypes, suggesting distinct, subclass-specific functional roles in parallel GPCR signaling pathways. In contrast, class I and II ORs were grouped into two and three sub-classifications, respectively, for one subtype of G_olf. In parallel OR signal processing, the response rapidity of helix-8-2^nd-Glu ORs via activation of G_olf suggests their key role during odor coding. Additionally, sniffer mice discriminated between 0.3 nL urine mixture odors of pre- and post-transurethral resection in individual patients with bladder cancer in an equal-occult blood diluted condition. Future analysis of urine mixtures may provide more robust biomarkers of bladder cancer than those of single individual urine samples.