Identification of common binding sites for calmodulin and inositol 1,4,5-trisphosphate receptors on the carboxyl termini of Trp channels

Homologues of Drosophila Trp (transient receptor potential) form plasma mem brane channels that mediate Ca2+ entry following the activation of phosphol ipase C by cell surface receptors, Among the seven Trp homologous found in mammals, Trp3 has been shown to interact with and respond to IP3 receptors (IP(3)Rs) for activation. Here we show that Trp4 and other Trp proteins als o interact with IP(3)Rs. The IP3R-binding domain also interacts with calmod ulin (CaM) in a Ca2+-dependent manner with affinities ranging from 10 nM fo r Trp2 to 290 nM for Trp6, In addition, other binding sites for CaM and IP( 3)Rs are present in the alpha but not the beta isoform of Trp4, In the pres ence of Ca2+, the Trp-IP3R interaction is inhibited by CaM, However, a synt hetic peptide representing a Trp-binding domain of IP(3)Rs inhibited the bi nding of CaM to Trp3, -6, and -7 more effectively than that to Trp1, -2, -4 , and -5, In inside-out membrane patches, Trp4 is activated strongly by cal midazolium, an antagonist of CaM, and a high (50 muM) but not a low (5 muM) concentration of the Trp-binding peptide of the IP3R. Our data support the view that both CaM and IP(3)Rs play important roles in controlling the gat ing of Trp-based channels. However, the sensitivity and responses to CaM an d IP(3)Rs differ for each Trp.