Cannabinoid GPCRs, ectopic olfactory GPCRs and TRP channels: a prespecified Baseline–Edit–Rescue framework for testing higher-order membrane-conditioned integration

Abstract Cell membranes are not mere platforms for signalling proteins; they can shape how receptor inputs are assembled into local responses. In membrane-rich microdomains, receptor identification and pathway mapping do not reveal the logic of a measured effect. That effect may arise from independent receptor activity, pairwise crosstalk or higher-order integration governed by membrane state. The Membrane-Encoded Chemosensory System (MECS) is introduced as a conceptual framework for addressing the inferential gap between receptor co-expression mapping and mechanistic crosstalk claims in territories with cannabinoid GPCRs, ectopic olfactory GPCRs and TRP channels. Its operational method, MECS Baseline–Edit–Rescue (MECS-BER), fixes one membrane prior, one locked proximal outcome and one three-arm candidate assembly. Eligibility gates test arm engagement and outcome competence. Combinatorial responses are analysed with κ, the third-order interaction under a pairwise-only null within a complete three-factor perturbation design, to distinguish lower-order explanation from higher-order interpretation and test edit–rescue reversibility. Deterministic matrices and simulations establish classification logic and tolerance handling; biological adjudication awaits fully compliant MECS-BER datasets. The workflow provides a prespecified and formalised methodological route, not biological proof of any specific receptor triad. It keeps nomination separate from adjudication and requires co-localisation, distal phenotypes, shared downstream signals and nonlinear mixtures to be tested against a locked proximal outcome before biological interpretation. Renal micro-niches specify prospective deployment across renin, transport, barrier and flow-sensitive calcium control without claiming validated cannabinoid–olfactory–TRP assemblies. Membrane lipids may shape both the signalling vocabulary of individual receptors and the local language through which receptors communicate.