Table 1:
Key tenets of the Remote Sensing and Signaling Theory.
| Remote Sensing and Signaling Theory Concepts |
|---|
| Proteins: Drug and other transporters, drug metabolizing enzymes (DMEs), nuclear receptors, kinases, and other regulatory proteins |
| Endogenous small molecules with “high informational content”: rate-limiting metabolites (e.g., dicarboxylates), signaling molecules (e.g., sex steroids, prostaglandins), nutrients (e.g., pantothenic acid), antioxidants (e.g., urate), gut microbiome products (e.g., indoxyl sulfate, secondary bile acids) |
| Regulated expression of transporters on apical and basolateral surfaces of polarized epithelial tissues, such as kidney, liver, intestine, choroid plexus, retina, and placenta (as well as endothelial cells) |
| Combinatorial possibilities of multi-, oligo-, and mono-specificity to (re)optimize metabolite levels at multiple scales (organelle, cell, tissue, organ, organ system, organism, multiple organisms) |
| Inter-organ small molecule remote communication (e.g., gut-liver-kidney) |
| Inter-organismal small molecule remote communication (e.g., gut microbiome-host, mother-fetus) |
| Representation as Remote Sensing and Signaling Network consisting of ~500–1000 proteins with hubs including multi-specific transporters, DMEs, and nuclear receptors |
| DMEs play a critical role by tagging small molecules with sulfate, glucuronide, and other groups for destinations in other cells/organs with specific drug transporter expression profiles |
| Evolutionary conservation of key gene families as well as network topology |
| The Remote Sensing and Signaling System functions in parallel and in tandem with other homeostatic systems (e.g., neuroendocrine, growth factor-cytokines, autonomic nervous system) |
| The Remote Sensing and Signaling System resets after perturbation (e.g., acute and chronic organ injury, metabolic disorders) to help restore homeostasis via transcriptional, post-translational and epigenetic mechanisms |
| Endogenous small molecule homeostasis by the Remote Sensing and Signaling System (Network) is viewed in terms of activity necessary to meet tens to hundreds of small, if sometimes conflicting, biological objectives. This in turn leads to optimization of levels of hundreds to thousands of metabolites and signaling molecules in cells, tissues, and body fluids |
| Major implications: biological basis for pharmacokinetics, drug-metabolite interactions, drug-induced metabolic diseases, treatment of complex metabolic disease, pharmacokinetic and other modeling |