Chemogenetics has been defined as a method by which proteins are engineered to interact with previously unrecognized small molecule chemical actuators (). Over the past two decades, a large number of chemogenetic (also known as “chemical genetic”; () platforms have been invented that have been useful for biologists in general and most especially for neuroscientists.

A number of protein classes ( Table 1 ) have been chemogenetically engineered including kinases (), non-kinase enzymes (), G protein-coupled receptors (GPCRs) (), and ligand-gated ion channels () (for recent review, see). Of these various classes of chemogenetically engineered proteins, the most widely used to date have been Designer Receptors Exclusively Activated by Designer Drugs (DREADDs) (), and this Neuron Primer is devoted to them.

Evolving the lock to fit the key to create a family of G protein-coupled receptors potently activated by an inert ligand.

Evolving the lock to fit the key to create a family of G protein-coupled receptors potently activated by an inert ligand.

Evolving the lock to fit the key to create a family of G protein-coupled receptors potently activated by an inert ligand.

Evolving the lock to fit the key to create a family of G protein-coupled receptors potently activated by an inert ligand.

Tailoring the active site of chemzymes by using a chemogenetic-optimization procedure: towards substrate-specific artificial hydrogenases based on the biotin-avidin technology.

How an Understanding of GPCR Molecular Pharmacology Facilitates the Appropriate Use of DREADD Technology

∗L) and promote the formation of a signaling complex (e.g., the “ternary complex”) consisting of (1) the active receptor, (2) an agonist, and (3) the heterotrimeric G protein (R∗LG) ( De Lean et al., 1980 De Lean A.

Stadel J.M.

Lefkowitz R.J. A ternary complex model explains the agonist-specific binding properties of the adenylate cyclase-coupled beta-adrenergic receptor. Samama et al., 1993 Samama P.

Cotecchia S.

Costa T.

Lefkowitz R.J. A mutation-induced activated state of the beta 2-adrenergic receptor. Extending the ternary complex model. ∗) in the absence of ligand. Further, this active state can spontaneously interact with G proteins to yield a binary signaling complex in the absence of ligand (R∗G) ( Samama et al., 1993 Samama P.

Cotecchia S.

Costa T.

Lefkowitz R.J. A mutation-induced activated state of the beta 2-adrenergic receptor. Extending the ternary complex model. Both full and partial agonists stabilize the active state (RL) and promote the formation of a signaling complex (e.g., the “ternary complex”) consisting of (1) the active receptor, (2) an agonist, and (3) the heterotrimeric G protein (RLG) (). In addition to the ligand-induced activation and inactivation of GPCRs, GPCRs can also spontaneously isomerize to an active state (R) in the absence of ligand. Further, this active state can spontaneously interact with G proteins to yield a binary signaling complex in the absence of ligand (RG) (). This active state in the absence of ligand is termed “constitutive activity.”

DeWire et al., 2007 DeWire S.M.

Ahn S.

Lefkowitz R.J.

Shenoy S.K. Beta-arrestins and cell signaling. An additional concern with DREADD technologies relates to issues of desensitization and subsequent receptor downregulation. Thus, following repeated dosing with a DREADD chemical actuator, one might observe diminished responses due to receptor desensitization and downregulation. This diminished response might be predicted because it is well known that GPCRs can be desensitized and subsequently internalized and downregulated following agonist-induced activation ().