biostudies-literatureNagai JNICHD NIH HHSNIDA NIH HHSNHLBI NIH HHSMedical Research CouncilNINDS NIH HHS2256-2274.e9https://www.ebi.ac.uk/biostudies/studies/S-EPMC8418870biostudies-literatureUnknown109(14)Astrocytes respond to neurotransmitters and neuromodulators using G-protein-coupled receptors (GPCRs) to mediate physiological responses. Despite their importance, there has been no method to genetically, specifically, and effectively attenuate astrocyte G_q GPCR pathways to explore consequences of this prevalent signaling mechanism in vivo. We report a 122-residue inhibitory peptide from β-adrenergic receptor kinase 1 (iβARK; and inactive D110A control) to attenuate astrocyte G_q GPCR signaling. iβARK significantly attenuated G_q GPCR Ca²⁺ signaling in brain slices and, in vivo, altered behavioral responses, spared other GPCR responses, and did not alter astrocyte spontaneous Ca²⁺ signals, morphology, electrophysiological properties, or NeuronSpecific and behaviorally consequential astrocyte G_q GPCR signaling attenuation in vivo with iβARK.PMC8418870R35 NS111583R01 DA047444R00 HL132882UKDRI-4007U54 HD087101K99 HL132882P30 NS062691R01 NS116589Gangwani MRGradinaru VNagai JSchumacher SMDiaz-Castro BBellafard AQu ZKhakh BSGolshani PCoppola GYu XOllivier MfalseSpecific and behaviorally consequential astrocyte G_q GPCR signaling attenuation in vivo with iβARK.Astrocytes respond to neurotransmitters and neuromodulators using G-protein-coupled receptors (GPCRs) to mediate physiological responses. Despite their importance, there has been no method to genetically, specifically, and effectively attenuate astrocyte G_q GPCR pathways to explore consequences of this prevalent signaling mechanism in vivo. We report a 122-residue inhibitory peptide from β-adrenergic receptor kinase 1 (iβARK; and inactive D110A control) to attenuate astrocyte G_q GPCR signaling. iβARK significantly attenuated G_q GPCR Ca²⁺ signaling in brain slices and, in vivo, altered behavioral responses, spared other GPCR responses, and did not alter astrocyte spontaneous Ca²⁺ signals, morphology, electrophysiological properties, or 2021-01-01T00:00:00Z2021 Jul2026-05-09T03:09:25.177Z2025-04-05T14:08:24.204ZS-EPMC84188703413914910.1016/j.neuron.2021.05.023