During evolution, TRPV1 has lost, retained or selected certain residues at Lipid-Water-Interface (LWI) and formed specific patterns there. The ratio of “hydrophobic-hydrophilic” and “positive-negative charged” residues at the inner LWI remains conserved throughout vertebrate evolution and play important role in regulating TRPV1 trafficking, localization and functions. Arg575 is an important residue as Arg575Asp mutant has reduced Capsaicin-sensitivity, surface expression, colocalization with lipid-raft markers, cell area, and increased cell lethality. This lethality is due to the disruption of the ratio between positive-negative charges there. Such lethality can be rescued by either using TRPV1-specfic inhibitor 5’-IRTX or by restoring the positive-negative charge ratio at that position, i.e. by introducing Asp576Arg mutation in Arg575Asp backbone. We propose that Arg575Asp mutant confers TRPV1 in a “constitutive-open-like” condition. These findings have broader implication in understanding the molecular basis of thermo-gating and channel-gating and the microenvironments involved in such process that goes erratic in different diseases. ### Competing Interest Statement The authors have declared no competing interest.

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