TRPV1 as a Central Point of Convergence in Post-Spike Syndrome Pathomechanisms of PEM/PENE, POTS, MCAS, and SFN, and a Phase-Based Therapeutic Framework

Kurt E Müller and Martina D Wagner

Abstract

Post-spike syndromes following SARS-CoV-2 infection and modRNA vaccination—post-exertional malaise/neuroimmune exhaustion (PEM/ PENE), postural orthostatic tachycardia syndrome (POTS), mast cell activation syndrome (MCAS), and small fiber neuropathy (SFN)—share a common molecular axis of convergence despite their divergent clinical presentations. We propose that the transient receptor potential vanilloid 1 (TRPV1) channel acts as a central sentinel receptor that detects the spike protein as an exogenous signal and translates it, via three parallel axes—an ion axis (Ca²+/Na+), a glutamate/N-methyl-D-aspartate (NMDA) axis, and a neuropeptide/immune axis (substance P/neurokinin-1 receptor)—into a shared mitochondrial dysfunction. Central to this model is the interplay between TRPV1-mediated Ca²+/Na+ influx, compensatory SERCA and Ca²+-activated potassium channel activity, mitochondrial Ca²+ uptake via the mitochondrial calcium uniporter (MCU) and the mitochondrial sodium–calcium exchanger (NCLX), and a downstream glutamatergic amplification loop converging on the NMDA receptor. Building on this mechanistic model, we develop a phase-based therapeutic framework (mast cell foundation, neuronal and synaptic braking, neuroinflammatory resolution), in which pharmacological, nutritional, and lifestyle interventions are mapped onto the corresponding steps of the cascade. The model generates testable mechanistic predictions and is conceptually situated within the exposome surveillance hypothesis.