The combination of surface plasmon resonance and mass spectrometry is emerging as a sensitive tool for the elucidation of protein-protein interactions. With the use of surface plasmon resonance-mass spectrometry, peptides, and brain extracts, we now report a novel interaction between the voltage-gated sodium channel type X alpha-subunit and caveolin-1, the central protein controlling caveolae formation. Surface plasmon resonance binding analyses show that this interaction involves amino acids 85-103 of voltage-gated sodium channel type X alpha-subunit and amino acids 81-100 of caveolin-1, a known scaffolding domain of caveolin-1. It is anticipated that the surface plasmon resonance-mass spectrometry approach utilized in this study will be important for the elucidation of protein-protein network analysis in native tissues including the brain.