Introduction: Impaired lower esophageal sphincter (LES) relaxation is the hallmark of achalasia esophagus and spastic motor disorders of the esophagus. On the other hand, excessive LES relaxation (transient LES relaxation) leads to reflux disease. Therefore, LES dysfunction contributes to significant morbidity and health related costs. Our current understanding is that the LES relaxation is neurogenic, mediated by vagus nerve which synapses with the inhibitory motor neurons of the myenteric plexus. Hypothesis: Our hypothesis is that the vagus nerve synapse with the excitatory nerves of the longitudinal muscles of the esophagus and it is the mechanical stretch caused by longitudinal muscle contraction that activates inhibitory motor neurons located in the myenteric plexus through a mechanosensitive (stretch-sensitive) mechanism. We will identify the molecular candidates for the mechanosensitive property of the myenteric neurons. Aim: The specific goals of our studies are: 1).To examine TRPV4 as a mechanosensitive molecule of the esophageal myenteric neurons (EMN); 2). To examine NCX1 as a mechanosensitive molecule of the EMN; 3).To determine if TRPV4 and NCX1 are synergistic in the mechanosensitivity of the EMN. Clinical Relationships: A large number of veterans suffer from reflux disease and spastic motor disorders of the esophagus and we believe that LES dysfunction plays a major role in both of the above. A better understanding of the neural control of esophageal peristalsis and LES relaxation is likely to lead to better treatment strategies in various esophageal motor disorders. Impact/Significance: We hope that an improved understanding of the mechanism of central and peripheral control of esophagus and LES motor function will results in better strategies to treat reflux disease and spastic disorders of the esophagus.