Tmem100 peptides and variants thereof and their use in treating or preventing diseases or conditions

1. A method for treating or preventing a condition associated with TRPA1 function or for which reduced TRPA1 activity can reduce the severity, comprising administering an effective amount of a Tmem100 mutant polypeptide, comprising administering to the cell an effective amount of a Tmem100 mutant polypeptide, wherein the Tmem100 mutant polypeptide comprises an amino acid sequence selected from the group consisting of: SEQ ID NO: 5, SEQ ID NO: 6, SEQ ID NO: 7, SEQ ID NO: 8, and SEQ ID NO: 17, thereby inhibiting TRPA1 function in the cell; or

a method of preventing, treating, or alleviating symptoms of a disease or condition associated with TRPA1 function or for which reduced TRPA1 activity can reduce the severity, comprising administering to a subject in need thereof a Tmem100 mutant polypeptide, wherein the Tmem100 mutant polypeptide comprises an amino acid sequence selected from the group consisting of: SEQ ID NO: 5, SEQ ID NO: 6, SEQ ID NO: 7, SEQ ID NO: 8, and SEQ ID NO: 17, thereby inhibiting TRPA1 function in the cell; or

a method of inhibiting TRPA1 function in a cell, comprising administering to the cell an effective amount of a Tmem100 mutant polypeptide, wherein the Tmem100 mutant polypeptide comprises an amino acid sequence selected from the group consisting of: SEQ ID NO: 5, SEQ ID NO: 6, SEQ ID NO: 7, SEQ ID NO: 8, and SEQ ID NO: 17, thereby inhibiting TRPA1 function in the cell.

2. The method of claim 1 wherein the TRPA1 function is an association with TRPV1.

3. The method of claim 2 , wherein the Tmem100 mutant polypeptide enhances the association of TRPA1 with TRPV1.

4. The method of claim 1 , wherein said TRPA1 function is an inward TRPA1-mediated current, an outward TRPA1-mediated current, TRPA1-mediated ion flux or TRPA1-mediated neuronal hyperexcitability.

5. The method of claim 1 , wherein the Tmem100 mutant polypeptide comprises a polypeptide with one or more alterations in the amino acid sequence of SEQ ID NO: 1 or SEQ ID NO: 2 wherein the one or more alterations in the amino acid sequences enhance association of TRPA1 and TRPV1 and inhibit TRPA 1.

6. The method of claim 1 , wherein the Tmem100 mutant polypeptide is provided to a cell and the cell is a sensory neuron.

7. The method of claim 6 , wherein the cell body of the sensory neuron resides in the dorsal root ganglia (DRG).

8. The method of claim 1 , used to prevent, treat, or alleviate symptoms of pain.

9. The method of claim 1 , used to prevent, treat, or alleviate symptoms of itch.

10. The method of claim 8 , wherein the pain is acute pain or chronic pain.

11. The method of claim 1 , wherein the Tmem100 mutant polypeptide is administered in combination with one or more agents.

12. The method of claim 1 , wherein the Tmem100 mutant polypeptide is administered in combination with one or more of a TRPV1 inhibitor, a TRPV3 inhibitor, a TRPV4 inhibitor, or a TRPM8 inhibitor.

13. A pharmaceutical composition for treating or preventing a condition involving activation of TRPA1 or for which reduced TRPA1 activity can reduce the severity, comprising an effective amount of a Tmem100 mutant polypeptide, wherein the Tmem100 mutant polypeptide comprises an amino acid sequence selected from the group consisting of: SEQ ID NO: 5, SEQ ID NO: 6, SEQ ID NO: 7 and SEQ ID NO: 8.

14. The pharmaceutical composition of claim 13 , wherein the Tmem100 mutant polypeptide comprises a polypeptide with one or more alterations in the amino acid sequence of SEQ ID NO: 1 or SEQ ID NO: 2 wherein the one or more alterations in the amino acid sequences enhance association of TRPA1 and TRPV1 and inhibit TRPA1.

15. An isolated cell-permeable polypeptide comprising an amino acid sequence selected from the group consisting of: SEQ ID NO: 5, SEQ ID NO: 6, SEQ ID NO: 7 and SEQ ID NO: 8, wherein the polypeptide is myristoylated or palmitoylated at each N-terminus.

16. An expression vector, which replicates in at least one of a prokaryotic cell and eukaryotic cell, comprising:

an isolated nucleic acid comprising a nucleotide sequence selected from the group consisting of: SEQ ID NO: 9, SEQ ID NO: 10, SEQ ID NO: 11 and SEQ ID NO: 12; or

expresses a polypeptide comprising an amino acid sequence selected from the group consisting of: SEQ ID NO: 5, SEQ ID NO: 6, SEQ ID NO: 7 and SEQ ID NO: 8.

17. A cell comprising an expression vector which replicates in at least one of a prokaryotic cell and eukaryotic cell, comprising:

an isolated nucleic acid comprising a nucleotide sequence selected from the group consisting of: SEQ ID NO: 9, SEQ ID NO: 10, SEQ ID NO: 11 and SEQ ID NO: 12; or

wherein the expression vector expresses a polypeptide comprising an amino acid sequence selected from the group consisting of: SEQ ID NO: 5, SEQ ID NO: 6, SEQ ID NO: 7 and SEQ ID NO: 8.

18. A method comprising culturing a cell in a cell culture medium, the cell comprising an expression vector which replicates in at least one of a prokaryotic cell and eukaryotic cell, wherein the expression vector comprises: an isolated nucleic acid comprising a nucleotide sequence selected from the group consisting of: SEQ ID NO: 9, SEQ ID NO: 10, SEQ ID NO: 11 and SEQ ID NO: 12; or comprises a nucleotide sequence encoding a polypeptide comprising an amino acid sequence selected from the group consisting of: SEQ ID NO: 5, SEQ ID NO: 6, SEQ ID NO: 7 and SEQ ID NO: 8.