SARS-CoV-2 spike and nicotinic acetylcholine receptors: a testable context-dependent hypothesis across acute and post-acute disease

Studies of SARS-CoV-2 spike and nicotinic acetylcholine receptors (nAChRs) have reported negative binding results, positive or mixed electrophysiological findings, and reduced receptor surface expression. These observations do not constitute a demonstrated discrepancy in binding affinity. We examine whether three measurable dimensions can explain part of the disagreement: the molecular preparation, receptor mechanism, and timing and compartment of exposure. The central hypothesis is that processing or redistribution of spike may alter the opportunity for nicotinic modulation and that appropriately located, active material could contribute to symptoms in a subset of post-acute disease. No study has demonstrated the complete pathway from spike processing through receptor-active human exposure to a clinical phenotype. Negative α7 experiments included isolated peptides and S1, so cleavage or S1 release cannot be assumed sufficient for activity. The S2-associated surface-expression mechanism requires intracellular co-expression and is distinct from extracellular S1 pharmacology. Antigen detection is treated as a reason to investigate exposure, not evidence of receptor occupancy. We separate experimental observations, mechanistic interpretations and clinical hypotheses, and specify results that would reject individual branches. A minimal programme would first test matched preparations, then establish receptor-specific activity of patient material at measured exposure, and only then examine longitudinal clinical relationships. ACE2/renin–angiotensin signalling and other disease mechanisms remain alternatives or potential interacting pathways. Overlapping symptoms after infection and vaccination justify comparison but do not establish an identical cause. This framework makes the proposed contribution of spike to nicotinic dysfunction testable without presenting it as a general explanation of COVID-19 or a basis for treatment.