Glucose-dependent trafficking of 5-HT3 receptors in rat gastrointestinal vagal afferent neurons

Background Intestinal glucose induces gastric relaxation via vagally mediated sensory-motor reflexes. Glucose can alter the activity of gastrointestinal (GI) vagal afferent (sensory) neurons directly, via closure of ATP-sensitive potassium channels, and indirectly, via the release of 5-hydroxytryptamine (5-HT) from mucosal enteroendocrine cells. We hypothesized that glucose may also be able to modulate the ability of GI vagal afferent neurons to respond to the released 5-HT, via regulation of neuronal 5-HT3 receptors. Methods Whole-cell patch clamp recordings were made from acutely dissociated GI-projecting vagal afferent neurons exposed to equiosmolar Krebs solution containing different concentrations of d-glucose (1.2520 mmol L-1) and the response to picospritz application of 5-HT assessed. The distribution of 5-HT3 receptors in neurons exposed to different glucose concentrations was also assessed immunohistochemically. Key Results Increasing or decreasing extracellular d-glucose concentration increased or decreased, respectively, the 5-HT-induced inward current and the proportion of 5-HT3 receptors associated with the neuronal membrane. These responses were blocked by the Golgi-disrupting agent Brefeldin-A (5 mu mol L-1) suggesting involvement of a protein-trafficking pathway. Furthermore, l-glucose did not mimic the response of d-glucose implying that metabolic events downstream of neuronal glucose uptake are required to observe the modulation of 5-HT3 receptor mediated responses. Conclusions & Inferences These results suggest that, in addition to inducing the release of 5-HT from enterochromaffin cells, glucose may also increase the ability of GI vagal sensory neurons to respond to the released 5-HT, providing a means by which the vagal afferent signal can be amplified or prolonged.