Junctional multiprotein signaling complexes in sensory neurons

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In order to perceive and evaluate the environment mammals are equipped with peripheral nerves (peripheral somatosensory system). These nerves run through our body and collect information about rigidity, warmth and chemical composition of the surrounding milieu and also about our own body's integrity. These nerves are equipped with various molecular sensors that respond to specific external stimuli, transforming these into the uniform electrical impulses ('action potentials') that are then sent to the brain for interpretation. Single somatosensory nerve often expresses a variety of different sensors or sensory mechanisms that respond to distinct stimuli, yet the output signals produced by a nerve are very similar. A major conundrum in the field is how different types of signals are specifically interpreted by a single sensory nerve cells; the main aim of this proposal is to shed light on this question. Based on the wealth of preliminary data and published work from our group and others we hypothesize that one mechanism for such intracellular signal specificity lies in the assembly of different intracellular signaling mechanisms into distinct, physically associated protein complexes. Such physical separation of one signaling machinery from another allows them to use common signaling events and messenger molecules without 'mixing up' the meaning of the message. We will focus on one such multiprotein complex which is responsible for body's detection of tissue inflammation (i.e. inflammatory pain). We have already established that there are intricate multiprotein signaling complexes in some sensory nerves that bring together receptors for chemical mediators of inflammation and some signaling proteins that are targeted by these receptors. However, hardly anything is known about the overall constitution of these complexes, functional arrangements of their components, relationships with other signalling mechanisms, whether these complexes are dynamic or static or whether these can be manipulated for therapeutic benefits. Our project aims to answer these intriguing questions. We have three specific aims: 1) to reveal molecular composition of the inflammatory multiprotein signaling complexes in sensory nerves; 2) to elucidate functional significance of these complexes; 3) to develop strategies for manipulations with complex integrity for scientific and therapeutic purposes. We developed a comprehensive and multidisciplinary approach in which fidelity, specificity and localization of neuronal communication mechanisms will be elucidated in their complexity. This approach combines cutting-edge methods such as Nobel Prize winning super-resolution microscopy, proteomics, molecular and structural biology approaches and in vivo studies. We are confident that this research will bring our understanding of mammalian sensory systems and, particularly, of inflammatory pain mechanisms, to a new level of insight. Importantly, our findings may shape new approaches for analgesic drug development and pain management.