Friday, April 18, 2025
4/18/2025
Mechanisms underlying stretch-evoked activation of esophageal vagal afferents - Stretch-sensitive esophageal vagal afferent nerves provide essential sensory feedback to brainstem interocep- tive and motor circuits that control swallow and esophageal peristalsis. Dysfunctional control causes dysphagia, ineffective motility, excessive reflux, and pain. Dysphagia is a risk factor for aspiration pneumonia in neurological and neuromuscular diseases; and excessive reflux causes heartburn in 20% of the US population, one third of which are refractory to therapy. Although the mechanosensitivity of esophageal vagal afferents has been char- acterized into low threshold and high threshold mechanoreceptor fibers, there is a fundamental gap in our un- derstanding of the receptors and/or ion channels responsible for mechanotransduction, action potential (AP) initiation and conduction in esophageal afferents. This significantly hinders our understanding of an essential physiological process in health and disease, prevents rational therapeutic targeting of its components in esoph- ageal dysfunction, and conceals serious esophageal side-effects for future therapies targeting excitability in pain, cough and epilepsy. This gap is due to two reasons: previous mechanosensitive channels have been shown to play limited roles, but Piezo channels have not been tested; and most studies of voltage-gated Na+ channels (NaV1s) required for vagal APs have focused on the cell body with its overwhelming NaV1.7 currents, rather than at the peripheral terminal or axon, thus have overlooked essential roles of NaV1.1, 1.2, 1.6 and 1.8. Our long- term goal is to exploit mechanisms of afferent feedback to improve function in esophageal disorders. The objec- tive here is determine the mechanosensitive channels and NaV1s responsible for transducing esophageal stretch into vagal afferent activation. Our central hypothesis is that stretch-evoked afferent activation is dependent on afferent Piezo channels, whose activation induces AP initiation at the esophageal peripheral terminal and AP conduction within vagal axons via unique interactions of multiple NaV1s. In Aim 1, we will identify the mechani- cally-sensitive receptors required for stretch-evoked activation of esophageal vagal afferents. Our data shows that Piezo2 and Piezo1 are required for mechanotransduction in these afferents. In Aim 2, we will determine the NaV1 channels required for the transduction of mechanical stretch into the initiation of AP from esophageal vagal afferent terminals. Our data shows that AP initiation depends on a combination of NaV1.1, 1.2, 1.6 and 1.7, via non-redundant cooperation with NaV1.8. In Aim 3, we will determine the NaV1 channels required for AP conduc- tion in esophageal vagal axons. Our data shows that NaV1.2, 1.6 and 1.7 cooperate with NaV1.8 in a frequency- dependent manner. Our technical innovations allowing for the study of AP terminal initiation and axonal conduc- tion separately were essential in the development of novel concepts of location-specific NaV1 isoform contribu- tions and of functional cooperation between NaV1.8 and other isoforms. This study will identify the ion channels responsible for the transduction of esophageal stretch into afferent activity, a process essential for life, provide targets for esophageal dysfunction and provide esophageal context for targeting excitability in other diseases.
HHS’ Tracking Accountability in Government Grants System (TAGGS) website provides access to detailed descriptions of grants, loans, aggregated direct payments and other types of financial assistance awarded by the HHS Operating Divisions (OPDIVs) and the Office of the Secretary Staff Divisions (STAFFDIVs).