Structural basis for sensory receptor function

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PROJECT SUMMARY This proposal leverages cephalopods as a uniquely suited model system to ask how sensory systems detect and discriminate diverse environmental signals. Octopuses, as representative cephalopods, use their flexible arms and semi-autonomous distributed nervous system to explore their surroundings at a distance by locally detecting and capturing prey. This unique “taste by touch” system is mediated by chemotactile receptors (CRs), which are structurally similar to nicotinic acetylcholine receptors, but are insensitive to neurotransmitters, and instead detect poorly soluble molecules to mediate contact-dependent aquatic sensation. Here, we will exploit cephalopod chemotactile systems to understand how subtle evolutionary modifications in single proteins facilitate a functional transition from neuronal signaling to environmental sensation. Our approach spans structural biology to animal behavior. First, in Aim 1, we propose to determine high resolution structures of ligand- bound and apo octopus CRs to analyze structural and biophysical underpinnings of sensory versus neurotransmitter receptor function. In Aim 2, we will extend our comparative approach to CRs in distinct cephalopods with specific behaviors. In contrast to octopuses that use arms for active exploration, cuttlefish are ambush predators that strike and capture unsuspecting prey with their eight arms and two long tentacles. We recently discovered CRs in cuttlefish, which detect distinct ligands, exhibit different voltage dependence, and enable unique behaviors. Here, we will extend our analyses to include structurally informed experiments to compare aspects of ligand binding, ion permeation, and channel gating to ask how receptor function is suited to particular organismal behaviors. Finally, we recently found that octopus sensory cells express diverse CR subunit combinations that can form homo- and heteropentameric ion channel complexes. Subunit composition alters ligand sensitivity and ion permeation to tune signal detection, transduction, and filtering to influence peripheral processing in the octopus’ unusual distributed nervous system. In Aim 3, we will analyze the structural basis by which heteromeric complexes alter biophysical properties of ligand binding, ion permeation, and channel gating. Collectively, these studies will reveal broad principles underlying the structural basis for sensory receptor function and the evolution of biological novelty. Moreover, comparisons between cephalopod CRs and related mammalian neurotransmitter receptors will define core channel architecture for insights regarding conserved pharmacological targets.