Activation of IP(3) receptors requires an endogenous 1-8-14 calmodulin-binding motif

Binding of IP(3) (inositol 1,4,5-trisphosphate) to the IP(3)-binding core (residues 224–604) of IP(3)Rs (IP(3) receptors) initiates opening of these ubiquitous intracellular Ca(2+) channels. The mechanisms are unresolved, but require conformational changes to pass through the suppressor domain (residues 1–223). A calmodulin-binding peptide derived from myosin light chain kinase uncouples these events. We identified a similar conserved 1-8-14 calmodulin-binding motif within the suppressor domain of IP(3)R1 and, using peptides and mutagenesis, we demonstrate that it is essential for IP(3)R activation, whether assessed by IP(3)-evoked Ca(2+) release or patch-clamp recoding of nuclear IP(3)R. Mimetic peptides specifically inhibit activation of IP(3)R by uncoupling the IP(3)-binding core from the suppressor domain. Mutations of key hydrophobic residues within the endogenous 1-8-14 motif mimic the peptides. Our results show that an endogenous 1-8-14 motif mediates conformational changes that are essential for IP(3)R activation. The inhibitory effects of calmodulin and related proteins may result from disruption of this essential interaction.