The GsDREADD-P2A-mCitrine knock-in (KI) mouse line allows for Cre recombinase-inducible expression of HA-GsD-mCitrine. Cre recombinase-mediated removal of the floxed-STOP cassette results in expression of two proteins: the yellow fluorescent protein variant mCitrine and a hemagglutinin epitope-tagged, mutant G protein-coupled receptor (GsD [also called rM3Ds or R-s]. GsD is a Gs-coupled rat muscarinic 3 DREADD modified to have its second and third intracellular loops replaced with the corresponding turkey &beta;1-adrenergic receptor sequences. Two amino acid substitutions (Y148C and A238G) have been added that abolish receptor affinity for the native ligand, acetylcholine (ACh), but allow receptor binding and subsequent activation by the small pharmacologically inert molecule clozapine-N-oxide (CNO). CNO binding to GsD induces the selective activation of the canonical G&alpha;s signaling pathway, effectively increasing intracellular cAMP levels. Homozygous GsDREADD-P2A-mCitrine mice are expected to be viable and fertile, though homozygous mice have not been utilized as breeders to date. Following Cre recombinase exposure (Gli1-CreERT2), mCitrine expression was not detectable in brain tissue by microscopy; however, immunohistochemical staining against the HA tag demonstrated a significant increase in HA-tagged protein expression in radial glia-like (RGL) cells after 2 daily injections of tamoxifen and 4 daily doses of CNO. These GsDREADD-P2A-mCitrine mice may be useful for chemogenetic/pharmacogenetic studies of receptor-specific functions or general downstream cellular signaling emanating from activation of an excitatory G protein-coupled receptor (GPCR).

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GsDREADD-P2A-mCitrine mice were designed to have Cre recombinase-inducible expression of a CAG promoter-driven HA-GsD-mCitrine from the Gt(ROSA)26Sor locus. Following Cre-mediated removal of an upstream floxed-STOP cassette, higher expression levels of HA-tagged GsD and mCitrine yellow fluorescent protein is observed. GsD (Gs-coupled DREADD) is a mutant G protein-coupled receptor (GPCR) that induces the canonical Gs pathway specifically following administration of the pharmacologically inert molecule clozapine-N-oxide (CNO). These GsDREADD-P2A-mCitrine mice may be useful for chemogenetic/pharmacogenetic studies of Gs-biased (cAMP) GPCR signaling.

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