Biophysical Society Thematic Meeting | Bucharest 2026

Biophysics of Membrane Reactions in Brian

Poster Abstracts

8-POS Board 8 MELANOCORTIN-4 RECEPTOR (MC4R) LOCALIZATION AND SIGNALING IN THE PRIMARY CILIA OF HYPOTHALAMIC NEURONS IS MODULATED BY THE NONVISUAL OPSIN 3 (ENCEPHALOPSIN OR OPN3) Ramses R. M. Nestor ; Elena Oancea; Brown University, Neuroscience, Providence, RI, USA Primary cilia, specialized organelles on the surface of most neurons, compartmentalize signaling pathways, including those mediated by G protein-coupled receptors (GPCRs), to regulate diverse neuronal functions. In hypothalamic paraventricular nuclear (PVN) neurons, the melanocortin-4 receptor (MC4R) localizes to primary cilia, where it signals via cAMP to regulate energy homeostasis. In humans, MC4R loss-of-function mutations are the most common monogenic cause of obesity. In mice, disruption of either MC4R signaling or its ciliary localization leads to severe obesity. Despite the importance of ciliary MC4R signaling, the mechanisms governing MC4R localization and signaling within this compartment remain poorly understood. We previously identified a subpopulation of hypothalamic PVN neurons that co-express MC4R and the non-visual opsin 3 (OPN3). We further demonstrated that OPN3 forms a molecular complex with MC4R and negatively regulates MC4R-evoked somatic cAMP signaling to promote food consumption. Here, we investigated the role of OPN3 in regulating MC4R ciliary localization and signaling. Using NIH3T3 fibroblasts and GT1-7 hypothalamic neurons, we show that co expression of OPN3 with MC4R leads, in a DNA ratio-dependent manner, to sequestration of MC4R at the plasma membrane and reduced accumulation in primary cilia. This redistribution is mediated, at least in part, by OPN3-MC4R complex formation. Functionally, using a genetically encoded cilia-targeted cAMP indicator in GT1-7 neurons, we found that increasing OPN3 expression significantly suppressed endogenous MC4R-evoked ciliary cAMP signaling. Together, these findings identify OPN3 as a modulator of MC4R localization and ciliary signaling, revealing a novel “push-and-pull” mechanism that fine-tunes MC4R signaling in hypothalamic circuits controlling energy balance.

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