Grant: Project Grant

Opioid abuse is a severe global crisis due to addiction and life-threatening side effects. Strategies to address this problem must occur on several fronts and have prompted considerable efforts to understand the mechanisms underlying opioid receptor control and activity. Opioids produce their effects primarily by activating the mu-opioid receptor (MOR), a G protein-coupled receptor (GPCR). For this, MOR modulates the subfamily of inhibitory G proteins consisting of G(i1-3), G(z), G(oA), and G(oB). G(o) is encoded by a gene named GNAO1 which can generate two proteins, G(oA) and G(oB). Although G(oA) and G(oB) are generated from the same gene, the mechanistic difference between their mode of action remains elusive. G(o) is the most expressed protein of the central nervous system. Remarkably, they are the least studied G proteins. Genetic studies have shown that it is directly linked to many neurological and movement disorders, cancers, and hyperalgesia. Genetic studies have shown an important role of GNAO1 in regulating MOR function and outcomes, including side effects. As G(oA) and G(oB) are encoded by the same gene, genetic studies that disrupt the gene lead to the loss of expression of both proteins. In an effort to better understand MOR signaling by each of the G proteins individually, we discovered that G(oA) and G(oB) behave entirely differently, which had never been demonstrated before. Our research uncovers unique refractory properties of G(oA) over all other G proteins, including the very similar G(oB). We, therefore, hypothesize that G(oA) is a gatekeeper to neuron excitation by acting as a "dial" or "brake" for MOR signaling and possibly other inhibitory receptors. This " brake " dysfunction makes the neuron too easy to stimulate, leading to side effects. Decoding the global function of G(oA) vis-à-vis MOR and other GPCRs could reveal critical insights into G(oA)-related movement disorders and physical dependence.