Desensitization of agonist-induced stimulation is considered a universal paradigm of seven-transmembrane (7TM) receptors. This concept is now challenged by our present findings showing that coupling with G₁₅, renders 7TM receptors resistant to β-arrestin-mediated desensitization. G₁₅ is a member of the G_q/11 subfamily of heterotrimeric G proteins that is known to couple with most 7TM receptors independently from their G protein coupling specificities. Accordingly, we show here that agonist stimulation of V2 vasopressin (V2R), δ-opioid (DOR), and β2-adrenergic (β2AR) receptors, individually co-expressed with the α-subunit of G₁₅ (G₁₅α in transfected COS-7 cells, increased the intracellular accumulation of inositol phosphates (IPs). Moreover, the R137H mutant of V2R, that being constitutively desensitized causes nephrogenic diabetes insipidus in humans, re-gained functional coupling to phospholipase C-β when co-expressed with G₁₅α in transfected COS-7 cells while remaining unresponsive to agonist-induced accumulation of IPs or cAMP when co-expressed with G_qα or G_sα, respectively. Furthermore, in COS-7 cells, G₁₅α-mediated IP accumulation induced by agonist stimulation of wild type V2R, DOR, and β2AR was totally refractory to desensitization induced by over-expressed β-arrestin-2, whereas endogenous G_qα-mediated stimulation of IPs by V2R was desensitized. Whether refractoriness to desensitization would also be proven for endogenous 7TM receptors coupled with G₁₅ a mechanism to generate sustained intracellular signals in certain physiological and pathological conditions would then be demonstrated.