Satellite Glial Cells Control Sensory Neuron Excitability via the Release of Fibulin-2

Abstract Pain remains a major clinical challenge, with current therapies often limited by low efficacy and adverse effects. While excitability of sensory neurons in the dorsal root ganglia (DRG) is central to pain signaling, accumulating evidence highlights the importance of non-neuronal cells in modulating neuronal activity. Here, we identify satellite glial cells (SGCs) as a source of Fibulin-2, an extracellular matrix glycoprotein with diverse roles in nervous system development and repair. Using SGC primary cultures and mass spectrometry, we demonstrate that Fibulin-2 is secreted by SGCs in part via extracellular vesicles. Electrophysiological assays reveal that application of recombinant Fibulin-2 to cultured sensory neurons reduces neuronal excitability by modulating Kv4-mediated currents. In vivo , loss of Fibulin-2 leads to reduced Kv4.2 and Kv4.3 expression and heightened mechanical, heat and cold sensitivity in mice. Our findings uncover a SGC-sensory neuron signaling mechanism modulating pain sensitivity, suggesting Fibulin-2 as a potential therapeutic target for pain management. Highlights Fibulin-2 is secreted by cultured SGCs via canonical and EV pathways Fibulin-2 reduces sensory neuron excitability and firing frequency Fibulin-2 acts by increasing Kv4-mediated potassium currents Selective Fibulin-2 loss in SGCs heightens mechanical and thermal sensitivity