Fri, Nov 20 (11.30 AM – 11.50 AM)

Biased Signaling at Multiple Mu Opioid Receptors Generated by Alternative Splicing of OPRM1 Gene
Most clinically used opioids such as morphine and fentanyl, as well as drugs of abuse like heroin, act through the mu opioid receptors. The single-copy mu opioid receptor gene, OPRM1, undergoes extensive alternative pre-mRNA splicing, creating multiple splice variants or isoforms that are conserved from rodent to human. One type of the OPRM1 splice variants are the full-length 7 transmembrane (7TM) C-terminal splice variants, which have identical receptor structures including entire binding pocket, but contain a different intracellular C-terminal tail resulted from 3’ alternative splicing. Biased signaling of GPCRs has been defined by evidences that different agonists can produce divergent signaling transduction pathways through a single receptor. We have demonstrated that a single mu agonist can induce differential G-protein or β-arrestin2 signaling through multiple 7TM splice variants. Particularly, exon 7-associated 7TM C-terminal variant showed greater β-arrestin2 bias for most mu agonists than MOR-1, an exon 4-associated variant, correlating with their roles in vivo suggested by using gene targeting mouse models. Our studies provide a new perspective on biased signaling at least for Oprm1, which perhaps is important for our understanding of the complex mu opioid actions in vivo where all the 7TM splice variants co-exist.

Fri, Nov 20 (2.00 PM – 2.20 PM)

Impaired Nuclear Calcium Signaling Attenuates CREB-Mediated Neuronal Clearance in Alzheimer’s Disease
Inhibition of the autolysosomal system is one of the earliest changes in Alzheimer’s disease (AD) brains. Consequent disruption of molecular trafficking and molecular clearance are causally linked to increased neuronal vulnerability and neurodegeneration. We find that a decrease of nuclear calcium levels and consequently cAMP response element-binding protein (CREB)-mediated expression of its target genes associated with the autolysosomal pathway is the underlying mechanism for attenuated molecular clearance and decreased neuroprotection in presenilin (PS) and Tau mutants. Expression of the CREB-target gene sestrin 2 (sesn2) in human AD neurons promotes autophagic clearance and neuronal survival under stress conditions. We hypothesize that PS1 and Tau mutants impair Ryanodine Receptor (RyR)-mediated control of nuclear calcium, therefore inhibiting CREB-mediated transcription of clearance genes, promoting buildup of neurotoxic proteins that accumulate in the AD brain. Our studies aim to characterize a novel pathway that drives formation of pathological hallmarks associated with AD. Induced pluripotent stem cell (iPSC)-derived human forebrain neurons and Drosophila melanogaster are used to assess the impact of nuclear calcium depletion and reduced pCREB signaling in molecular clearance during AD onset and progression. Nuclear calcium depletion in PS and Tau mutant neurons add an important dimension to the long-standing calcium hypothesis of AD.