Molecular mechanism of hyperactivation conferred by a truncation of TRPA1

Avnika Bali, Samantha P. Schaefer, Isabelle Trier, Alice L. Zhang, Lilian Kabeche and Candice E. Paulsen ()
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Avnika Bali: Yale University
Samantha P. Schaefer: Yale University
Isabelle Trier: Yale University
Alice L. Zhang: Yale University
Lilian Kabeche: Yale University
Candice E. Paulsen: Yale University

Nature Communications, 2023, vol. 14, issue 1, 1-15

Abstract: Abstract A drastic TRPA1 mutant (R919*) identified in CRAMPT syndrome patients has not been mechanistically characterized. Here, we show that the R919* mutant confers hyperactivity when co-expressed with wild type (WT) TRPA1. Using functional and biochemical assays, we reveal that the R919* mutant co-assembles with WT TRPA1 subunits into heteromeric channels in heterologous cells that are functional at the plasma membrane. The R919* mutant hyperactivates channels by enhancing agonist sensitivity and calcium permeability, which could account for the observed neuronal hypersensitivity-hyperexcitability symptoms. We postulate that R919* TRPA1 subunits contribute to heteromeric channel sensitization by altering pore architecture and lowering energetic barriers to channel activation contributed by the missing regions. Our results expand the physiological impact of nonsense mutations, reveal a genetically tractable mechanism for selective channel sensitization, uncover insights into the process of TRPA1 gating, and provide an impetus for genetic analysis of patients with CRAMPT or other stochastic pain syndromes.

Date: 2023
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DOI: 10.1038/s41467-023-38542-1

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