Molecular Mechanisms of Integrative Signal Transduction

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Abstract Our research approach is to identify and characterize signaling mechanisms in specialized cell types as a means to understand mechanistic underpinnings of various physiological systems. This proposal leverages two uniquely-suited model systems to ask how cells detect and discriminate diverse environmental signals: 1) Sharks and skates detect and discriminate incredibly weak and specific electric fields using specialized electroreceptor cells. By exploiting this unique model system, we will ask how cells are molecularly tuned to filter and select among the subtle differences that specify the most salient environmental signals. Indeed, these fishes discriminate between small bioelectric signals, such as those from prey or mates, based on their physiological state. Furthermore, related modulatory hormones can regulate signal detection. Our recent studies have provided insight regarding the molecular basis of electroreception and suggest that specific ion channel properties contribute how incoming signals are filtered. Here, will we investigate how electroreceptor protein and cellular properties are modulated by physiological state to affect cellular signal transduction. We will use genetic profiling, electrophysiological, and expression cloning methods to probe hormone-induced cellular signaling cascades and their contribution to cellular electrical tuning. We will then leverage these defined signaling cascades to ask whether in vivo modulation of cellular tuning determines frequency selectivity in behaving animals. This approach will reveal how integrative cellular tuning contributes to signal discrimination. 2) In a second project, we will probe mechanisms of signal filtering in octopus arms, which are used as flexible sentinels that allow these animals to explore their surroundings at a distance by using a unique contact- dependent form of ‘taste by touch’ chemosensation. Furthermore, octopus arms are capable of processing this multimodal sensory information, independent of the centralized brain, to produce sophisticated behaviors. Our studies will use single-cell genetic profiling, physiological, protein structure-function, and natural product chemistry approaches to identify sensory receptors and their properties, signal transduction cascades, and intrinsic electrical properties used by specialized cells within arms that facilitate sensation. We will then independently or simultaneously activate these receptors and signaling cascades to ask how individual receptor proteins integrate information to produce specific cellular responses and organismal behaviors. This approach will allow us to determine how single cells detect and transduce multiple stimuli as distinct cellular outputs to govern organismal function. These integrative studies span multiple specialized cell types, tissues, and organisms to increase our understanding of the basic cell biology underlying signal transduction.