Molecular Mechanisms of Delta-2 Receptor Dysfunction in Neurological Diseases

The cerebellum is critical for regulating movement, coordination, and motor learning. Its functions rely on specialized neurons called Purkinje cells, which have highly branched dendrites, enabling integration of many synaptic inputs. The delta-2 type ionotropic glutamate receptor (GluD2) is fundamental for synapse formation and maintenance in Purkinje cells, where it is enriched. Dysregulation or mutation of GluD2 is implicated in several neurological and neurodevelopmental disorders, including cerebellar ataxia, autism spectrum disorder, and schizophrenia. However, the mechanisms by which patient mutations dysregulate GluD2 function are unclear, and there are no current pharmacologic strategies targeting this receptor. Thus, there is a significant gap in mechanistic understanding and therapeutic potential. A major barrier to understanding GluD2’s role in pathophysiology has been the longstanding ambiguity in its function. Despite GluD2 being in the ligand-gated ionotropic glutamate receptor (iGluR) family, whether GluD2 maintains iGluR-like ligand-gated activity has been debated because of a lack of direct functional evidence and no high-resolution structures of the full-length receptor. New data from our lab resolves this uncertainty and shows that human GluD2 is a bona fide ligand-gated ion channel through precision electrophysiology and structural biology. This gives us a unique foundation to understand the molecular consequences of pathophysiological mutations directly in human GluD2. In this work, we will define how disease-associated mutations perturb GluD2 function and architecture at the molecular level. We will investigate how cerebellar ataxia mutations in the human GluD2 amino terminal domain (Aim 1), ligand binding domain (Aim 2), and transmembrane domain (Aim 3) alter the receptor with an integrated biophysical approach – including single channel bilayer recordings, cryo-electron microscopy, and precision biochemistry. This will uncover how the mutations affect GluD2 structure, function, allostery, and pharmacology. The findings from this proposal will deliver a mechanistic atlas of human GluD2 dysfunction by bridging receptor function and architecture in both health and disease. Further, the data will provide a mechanistic, molecular framework for understanding GluD2-linked neurological disorders and will lay the groundwork for future structure- based therapeutic strategies against this critical disease target. Project Number: 1R01NS148147-01 | Fiscal Year: 2026 | NIH Institute/Center: National Institute of Neurological Disorders and Stroke (NINDS) | Principal Investigator: Edward Twomey | Institution: JOHNS HOPKINS UNIVERSITY, BALTIMORE, MD | Award Amount: $388,646 | Activity Code: R01 | Study Section: Biochemistry and Biophysics of Membranes Study Section[BBM] View on NIH RePORTER: https://reporter.nih.gov/project-details/11340619