Tyr-167/Trp-168 in type 1/3 inositol 1,4,5-trisphosphate receptor mediates functional coupling between ligand binding and channel opening.

ABSTRACT: The N-terminal ?220-amino acid region of the inositol 1,4,5-trisphosphate (IP(3)) receptor (IP(3)R)/Ca(2+) release channel has been referred to as the suppressor/coupling domain because it is required for both IP(3) binding suppression and IP(3)-induced channel gating. Measurements of IP(3)-induced Ca(2+) fluxes of mutagenized mouse type 1 IP(3)R (IP(3)R1) showed that the residues responsible for IP(3) binding suppression in this domain were not essential for channel opening. On the other hand, a single amino acid substitution of Tyr-167 to alanine completely impaired IP(3)-induced Ca(2+) release without reducing the IP(3) binding activity. The corresponding residue in type 3 IP(3)R (IP(3)R3), Trp-168, was also critical for channel opening. Limited trypsin digestion experiments showed that the trypsin sensitivities of the C-terminal gatekeeper domain differed markedly between the wild-type channel and the Tyr-167 mutant under the optimal conditions for channel opening. These results strongly suggest that the Tyr/Trp residue (Tyr-167 in IP(3)R1 and Trp-168 in IP(3)R3) is critical for the functional coupling between IP(3) binding and channel gating by maintaining the structural integrity of the C-terminal gatekeeper domain at least under activation gating.

SUBMITTER: Yamazaki H 

PROVIDER: S-EPMC2975230 | biostudies-literature | 2010 Nov

REPOSITORIES: biostudies-literature