GPCR crosstalk beyond obligate dimerisation: Effector coincidence detection, compartmentation, and pharmacological...

G protein-coupled receptors (GPCRs) classically signal through cognate heterotrimeric G proteins to regulate second messengers such as cyclic adenosine monophosphate (cAMP) and intracellular Ca²⁺. Yet when two GPCRs are co-expressed, their combined activation can generate emergent outputs, including atypical Ca²⁺ mobilisation, non-linear cAMP responses, and cross-antagonism, that do not occur when either receptor is stimulated alone. Such phenotypes are often attributed to heteromerisation or higher-order receptor complexes. Here, we show that many of these behaviours can be parsimoniously explained by downstream effector integration which may not require obligate GPCR dimers. We focus on membrane adenylyl cyclases (mACs) and phospholipase Cβ (PLCβ) isoforms as multi-input integrators that decode convergent Gα_s/olf, Gα_i/o, Gα_q/11, Gβγ, Ca²⁺/calmodulin, and kinase signals according to isoform-specific regulatory logic and subcellular organisation. We also highlight how Gβγ dimers are not generic signalling by-products, but selective effectors whose actions depend on subunit composition, effector identity, and microdomain context. Using D₁-D₂, 5-HT₂A-mGlu₂, A₂A-D₂, and D₂-GHSR as case studies, we show how paradigmatic "heteromer" phenotypes can be reframed as effector-level coincidence detection and compartmentalised crosstalk, and we outline experimental strategies to distinguish receptor-receptor allostery from shared-effector integration.