G Protein Signaling in CNS Disorders
Tuesday April 05, 2022
Eastern Time (ET)
University of Alabama
Icahn School of Medicine at Mount Sinai
This session will focus on recently identified roles of G protein signaling components in brain disorders, pointing to novel therapeutic pathways. Translational studies highlight the essential role of regulator of G protein signaling 4 in the maintenance of chronic pain states, the importance of spinophilin/coffilin interaction in post traumatic stress disorders, the impact of striatal cAMP signaling components on movement disorders and the impact of Gβγ–SNARE interaction on restoration of the release of hormones and neurotransmitters.
- Vanderbilt University
Disabling Gβγ-SNARE Interaction Disrupts GPCR-mediated Presynaptic Inhibition Leading to Physiological and Behavioral Phenotypes
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.
- Icahn School of Medicine at Mount Sinai
A Key Role of RGS4 in the Maintenance of Chronic Pain
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.
- University of Alabama
Activation of a Novel α2AAR-spinophilin-cofilin Axis Determines the Effect of α2 Adrenergic Drugs on Fear Memory Reconsolidation
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.
- Augusta University, Medical College of Georgia
G protein Signaling in Motor Behavior
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.
Talks will be selected from submitted abstracts.