Activation of Trp3 by inositol 1,4,5-trisphosphate receptors through displacement of inhibitory calmodulin from a common binding domain

Mammalian homologues of Drosophila Trp form plasma membrane channels that m ediate Ca2+ influx in response to activation of phospholipase C and interna l Ca2+ store depletion. Previous studies showed that human Trp3 is activate d by inositol 1,4,5-trisphosphate (IP3) receptors (IP(3)Rs) and identified interacting domains, one on Trp and two on IP3R. We now find that Trp3 bind s Ca2+-calmodulin (Ca2+/CaM) at a site that overlaps with the IP3R binding domain. Using patch-clamp recordings from inside-out patches, we further sh ow that Trp3 has a high intrinsic activity that is suppressed by Ca2+/CaM u nder resting conditions, and that Trp3 is activated by the following: a Trp -binding peptide from IP3R that displaces CaM from Trp3, a myosin light cha in kinase Ca2+/CaM binding peptide that prevents CaM from binding to Trp3, and calmidazolium, an inactivator of Ca2+/CaM. We conclude that inhibition of the inhibitory action of CaM is a key step of Trp3 channel activation by IP(3)Rs.