Signaling Microdomains Define the Specificity of Receptor-Mediated InsP3 Pathways in Neurons

AbstractM1 muscarinic (M1AChRs) and B2 bradykinin (B2Rs) receptors are two PLCβ-coupled receptors that mobilize Ca2+ in nonexcitable cells. In many neurons, however, B2Rs but not M1AChRs mobilize intracellular Ca2+. We have studied the membrane organization and dynamics underlying this coupling specificity by using Trp channels as biosensors for real-time detection of PLCβ products. We found that, in sympathetic neurons, although both receptors rapidly produced DAG and InsP3 as messengers, only InsP3 formed by B2Rs has the ability to activate IP3Rs. This exclusive coupling results from spatially restricted complexes linking B2Rs to IP3Rs, a missing partnership for M1AChRs. These complexes allow fast and localized rises of InsP3, necessary to activate the low-affinity neuronal IP3R. Thus, these signaling microdomains are of critical importance for the induction of selective responses, discriminating proinflammatory information associated with B2Rs from cholinergic neurotransmission