How cannabis receptors switch between opposite cellular responses

Protein kinase C (PKC) is classically viewed as a downstream effector of Gq/11-coupled G protein-coupled receptors (GPCRs), which activate phospholipase C to generate the diacylglycerol and Ca2+ signals required for PKC activation. However, several non-Gq/11 GPCRs have also been reported to activate PKC, a finding that has remained mechanistically unresolved. Here, we asked whether this unresolved question is determined not by receptor class itself, but by the signaling bias engaged downstream of receptor activation. Biased variants of the Gi/o-coupled dopamine D2 receptor (D2R), together with pharmacological perturbation and biochemical analyses, were used to compare G protein-biased and arrestin-biased pathways leading to PKCβII regulation. We found that G protein-biased, but not arrestin-biased, signaling selectively promotes PKCβII activation through a spatially organized multistep pathway. In this pathway, released Gβγ facilitates nuclear entry of PKCβII, where Mdm2-mediated ubiquitination appears to support subsequent activating steps and plasma membrane translocation. Upstream, this pathway depends on EGFR transactivation, which links receptor activation to convergent PI3K-PDK1 and PLCγ-DAG signaling. In contrast, arrestin-biased signaling suppresses PKCβII activation by redirecting Mdm2 toward preferential ubiquitination of arrestin3, thereby limiting PKCβII access to this regulatory pathway. Similar signaling logic was observed for the dopamine D3 receptor and cannabinoid CB1 receptor. These findings show that PKCβII activation downstream of non-Gq GPCRs is determined by signaling bias rather than by canonical receptor coupling alone, and identify competitive Mdm2-mediated ubiquitination as a mechanism linking biased GPCR signaling to differential PKC output.