Structure-Function and Signaling of Glutamate Delta 1 in Pain Mechanism

Creighton University, Omaha NE

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Abstract

Summary: Pain affects more than 100 million Americans producing devastating effects including long-term disabilities, mental health comorbidities and drug dependence as well as enormous economic burden. Available medications for chronic pain are not always effective and may have abuse liability. There is an urgent need to identify novel mechanisms for the treatment of chronic pain. A large body of evidence supports a role of plasticity of parabrachio-amygdala glutamatergic synapses in chronification of pain, but the underlying mechanisms are not fully understood. We have recently demonstrated a critical role of glutamate delta 1 receptor (GluD1; gene GRID1: UniProt Q9ULK0) and its synaptogenic binding partner cerebellin 1 (Cbln1) at the parabrachio-amygdala synapses in inflammatory and neuropathic pain. GluD1 is a member of the ionotropic glutamate receptor family but is unusual because it lacks typical ligand-gated ion channel activity and instead plays a critical role in synapse formation/maintenance by forming a trans-synaptic GluD1-Cbln1-Neurexin triad. We found a downregulation of GluD1-Cbln1 signaling in pain states and a contrasting increase in AMPA receptor subunit expression. Importantly, we found that injection of recombinant Cbln1 into the central amygdala normalized the changes in GluD1 and AMPA receptor expression and neuronal hyperexcitability in the central amygdala and also mitigated averse and affective behaviors in pain models. These results demonstrate a role of GluD1- Cbln1 signaling in pain-induced plasticity. In additional studies we found that the analgesic effect of recombinant Cbln1 was inhibited by D-serine. An increase in D-serine levels has been proposed to exacerbate nocifensive behaviors primarily via a NMDA receptor-dependent mechanism. However, D-serine binds to the ligand binding domain of GluD1 and produces conformational changes in the receptor. Recent studies also report ion channel pore activity of GluD1 in native system potentially trigged by activation of metabotropic receptors and modulated by D-serine binding. The contribution of D-serine binding to GluD1 and potential ion channel pore activity of GluD1 to pain mechanisms is unknown. The goal of the proposed studies is to examine the structure-function relationship of GluD1 specifically probing the function of ligand binding domain and ion channel pore of GluD1 in amygdala pain mechanisms. Two aims are proposed; Aim 1 will examine the regulation of analgesic effect of recombinant Cbln1 by D-serine interaction with GluD1. Aim 2 will examine the ion channel function of GluD1 in relation to pain mechanism. This project is significant because it will identify a novel mechanism by which the enigmatic GluD1 may contribute to chronic pain. The expected outcomes may provide critical information to develop new therapeutic approaches for chronic pain by targeting the ligand binding domain or ion channel pore of GluD1.