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Research ArticleArticle

Proteinase-Activated Receptor-2: Key Role of Amino-Terminal Dipeptide Residues of the Tethered Ligand for Receptor Activation

Bahjat Al-Ani, Kristina K. Hansen and Morley D. Hollenberg
Molecular Pharmacology January 2004, 65 (1) 149-156; DOI: https://doi.org/10.1124/mol.65.1.149
Bahjat Al-Ani
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Kristina K. Hansen
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Morley D. Hollenberg
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Abstract

Tryptic cleavage of proteinase-activated receptor-2 (PAR2) causes the unmasking of a tethered receptor-activating sequence, S37LIGRLDTP.... We sought to determine, in the amino-terminal sequence of the PAR2 tethered ligand, the key amino acid residues that are responsible for receptor activation. Using site-directed mutagenesis, nine PAR2 mutants with alanine substitutions in the first six amino acids of the tethered ligand, S37LIGRL42..., were prepared: PAR2S37A, PAR2L38A, PAR2I39A, PAR2G40A, PAR2R41A, PAR2A37-38, PAR2A39-42, PAR2A37,39-42, and PAR2A37-42, along with the reverse-sequence construct, PAR2L37S38. These mutants, together with wild-type PAR2(PAR2wt), were expressed in Kirsten virus-transformed rat kidney cells and were then assessed for receptor-mediated calcium signaling upon activation by trypsin and by receptor-activating peptides like SLIGRL-NH2. In addition, the release of the N-terminal receptor sequence that is cleaved from PAR2 by trypsin activation was monitored in the above cell lines using a site-targeted anti-receptor antibody. All PAR2 constructs were activated by SL-NH2, and all mutated tethered ligand sequences were unmasked by trypsin. However, differential activation of the receptor by trypsin in these mutants was observed: PAR2 mutants PAR2A37-38 and PAR2L37S38, in which the first two amino-terminal tethered ligand residues (S37L38) are either changed to alanines or reversed, yielded little or no response to trypsin, nor did PAR2A37,39-42. However, trypsin activated all other constructs. We conclude that the amino-terminal tethered ligand dipeptide sequence S37L38 plays a major role in the activation of PAR2.

  • Received June 27, 2003.
  • Accepted September 29, 2003.
  • The American Society for Pharmacology and Experimental Therapeutics
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Molecular Pharmacology: 65 (1)
Molecular Pharmacology
Vol. 65, Issue 1
1 Jan 2004
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Research ArticleArticle

Proteinase-Activated Receptor-2: Key Role of Amino-Terminal Dipeptide Residues of the Tethered Ligand for Receptor Activation

Bahjat Al-Ani, Kristina K. Hansen and Morley D. Hollenberg
Molecular Pharmacology January 1, 2004, 65 (1) 149-156; DOI: https://doi.org/10.1124/mol.65.1.149

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Research ArticleArticle

Proteinase-Activated Receptor-2: Key Role of Amino-Terminal Dipeptide Residues of the Tethered Ligand for Receptor Activation

Bahjat Al-Ani, Kristina K. Hansen and Morley D. Hollenberg
Molecular Pharmacology January 1, 2004, 65 (1) 149-156; DOI: https://doi.org/10.1124/mol.65.1.149
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