The SNAP25Δ3 mutation results in inhibited Gβγ-SNARE binding and diminished Gβγ competition with synaptotagmin 1 for binding sites on SNARE complexes. SNAP25Δ3 homozygote mice exhibit deficits in presynaptic inhibition by receptors that work directly on the SNARE complex such as 5-HT1b and α2a adrenergic receptors. Simultaneously stimulating receptors that work through this mechanism and through inhibition of calcium entry show synergistic inhibitory effects. Our studies show that Gi/o-coupled GPCR-mediated inhibition of exocytosis through the Gβγ-SNARE interaction is a crucial component of numerous physiological and behavioral processes.

Regulator of G protein signaling 4 (RGS4) is a potent modulator of GPCR signal transduction that is expressed in several nociceptive circuits. RNA Scope analysis shows that RGS4 is selectively expressed in Mrgprd polymodal nociceptors in the dorsal root ganglia (DRG) and its expression is robustly increased under prolonged pain states. We use advanced genetic mouse models for regional and temporal inactivation or overexpression of RGS4 in specfic nociceptive circuits to demonstrate a role of RGS4 in the maintenance of chronic neuropathic pain states. Single nucleus RNA Sequencing highlights unique pathways affected by RGS4 knockout and provide directions for novel therapeutic targets.

Post-pandemic posttraumatic stress disorder (PTSD) has emerged as a major neuropsychiatric component of the post-acute COVID-19 syndrome, yet the current pharmacotherapy for PTSD is limited. Our studies, using both genetically modified mice and human induced pluripotent stem cell-derived neurons, reveal a novel α2A adrenergic receptor (α2AAR)-spinophilin-cofilin axis in the hippocampus that is critical for regulation of contextual fear memory reconsolidation. Our results inform interpretation of differential clinical observations of different α2A agonists on PTSD, and suggest that modulation of dendritic spine morphology may represent an effective strategy for the development of new pharmacotherapies for this devestating disease.

Many GPCRs/G proteins couple to cAMP signaling, establishing a highly sensitive system fine-tuned by additional regulators and modifiers, which adjusts neuronal activity. Data over the years have shown that mutations in transducers and regulators of cAMP cascade, many of which are highly expressed in the striatum, are connected to hyperkinetic movement disorders. This emerging genetic insight provides a framework to reveal new causal relationships between molecular players. The talk will cover recent work on the mechanistic role of Gαo in regulating striatal cAMP signaling essential for motor behavior as well as our latest efforts in understanding cAMP modifiers that disrupt movement.