Pharmacosynthetics and the Cell-Type-Specific Control of Neuronal Signaling.

摘要

Pharmacology, in its broadest interpretation, is defined as the study of drug action. In modern neuropsychopharmacology, there is a conceptual boundary between the "drug" and the "action", with the drug itself on one side and signal transducer (receptor), the signal transduction cascade (effector proteins, second messengers), the cellular response (transcriptional regulation, activity modulation), the organ response (brain circuitry modulation), and, finally, the whole organism response (behavior) on the other. In other words, pharmacology has structured itself around the idea that the exogenous molecule (the drug) encodes a "signal" leading to everything on the other side including, in extreme instances, a physiological response. The inference is that engaging a particular signal transduction pathway in a defined cell type leads inexorably to a prototypic physiological response. Here, I suggest that the invention of synthetic ligand—GPCR pairs (aka DREADDs, RASSLS, `pharmacogenetics') permits the study of pharmacology using a shifted equation: with the signal transduction elements moved to the left and, subsequently, under experimental control. For the purposes of disambiguation and to clarify this approach as a creation of pharmacological manipulation, I present the term pharmacosynthetics to describe what has heretofore been called pharmacogenetics or chemicogenetics. In this document I will review previous work utilizing this technology, present my work validating a variation of this technology in a heretofore untested cellular context, and provide a perspective on how this technology can advance the field of pharmacology.