The Cost Is Not the Constraint: Evolutionary Accessibility and the No-Waiting Region in GPCR-Class Signalling

Complex cellular traits are often described as energetically inaccessible to unicellular lineages, but this explanation is persuasive only if the proposed burden is large enough to be visible to selection. This article tests that condition for a deliberately demanding case: a metazoan-style G-protein-coupled receptor (GPCR) signalling unit considered as a possible molecular substrate for reward-like computation in unicellular organisms. The analysis combines explicit energetic accounting with a drift-barrier formulation in which 1/(2Nₑ) is used as a selection-visibility scale rather than a hard fixation gate. A complete receptor, heterotrimeric G protein, arrestin, GRK and effector unit contains approximately 2,700 residues. At 10⁴ copies per cell and a yeast-scale lifetime energy budget, its standing cost is approximately 0.22% of the cellular budget per generation, compared with approximately 0.04% for a bacterial two-component sensor. Monte Carlo exploration of the stated parameter space places GPCR-class systems above the visibility boundary in 55.8% of draws, versus 73.9% for two-component sensors. Cost magnitude and microbial effective population size therefore do not explain the absence of GPCR-based reward computation. The operative constraint is path-dependent: standing cost is paid whenever the apparatus is expressed, whereas benefit is realised only when signalling is coupled to a fitness-relevant output. Under maintained expression, absent compensating function and Nₑc ≫ 1, a fully uncoupled intermediate enters a no-waiting region in which fixation is exponentially suppressed relative to neutrality. Evolution can avoid this region through co-option, duplication and dosage buffering, promiscuous coupling or constructive neutral evolution. Fungal nutrient and pheromone receptors and Dictyostelium cAMP receptors are consistent with this prediction because their transduction is coupled immediately to growth, mating, aggregation or development. The framework supplies falsifiable comparative and experimental predictions without denying unicellular cognition.