Lipid signaling in cardiovascular afferent transmission

Project SummaryTransient Receptor Potential Vanilloid Type 1 Receptors (TRPV1) are present in the central terminals of cranialvisceral afferents including arterial baroreceptors and airway afferents within the solitary tract nucleus (NTS)but the function of central TRPV1 is unclear. TRPV1 is a calcium channel with three separate ?openers?vanilloids, pH, and heat. Our recent cellular investigations demonstrate that TRPV1 calcium controls anindependently regulated pool of glutamate vesicles that is distinct from the pool of vesicles released by actionpotentials. TRPV1-operated vesicles generate spontaneous excitatory synaptic events (EPSCs). Actionpotential evoked EPSCs are triggered by voltage activated calcium channels separately from TRPV1-operatedglutamate release. Cooling to unphysiologically low temperatures 30°C suppresses TRPV1 release andvanilloid agonists sensitize thermal sensitivity. The present proposal stems from the observation that in animalsfed a high fat diet (HFD), blockade of TRPV1 receptors within medial NTS reduces blood pressure and heartrate. Animals fed control diets do not respond to TRPV1 blockade suggesting an endogenous lipid agonistinduced in NTS by the HFD. We will examine the mechanisms by which ST TRPV1 drives glutamatetransmission normally and during exposure to a HFD. Our in vivo preliminary results suggest that HFDgenerates a vanilloid-like mediator which controls afferent triggered reflex function within NTS. The ResearchPlan proposes to establish the mechanisms of action of vanilloids in ST afferent transmission with a focus onCNS function in aortic baroreflex control. Our global hypothesis proposes that ST TRPV1 serves as a focalintegrator of multiple signals in NTS with a primary reporting output of glutamate release. The Specific Aimswill investigate whether TRPV1-operated glutamate activates metabotropic glutamate receptors on GABArelease, whether postsynaptic depolarization modulates presynaptic TRPV1 mediated glutamate release,whether B-type GABA receptors alter myelinated baroreceptor transmission during HFD and how TRPV1activation in NTS during HFD alters baroreflex responses. My laboratory has extensive experience with TRPV1mechanisms in peripheral baroreceptors, baroreceptor reflexes, and central ST transmission. We will rely onmethods including electrophysiological, live cell imaging, dye tracing and assays of whole animal reflexcharacteristics to understand TRPV1 function from cell to reflex. We will team with the Madden lab for wholeanimal assessments. The proposed research will help us to better understand the normal basis of these neuralcontrol mechanisms as well as identify pathophysiological changes and shed light on homeostatic control thatinclude consequences for central nervous system inflammation, hypertension, stroke, metabolic syndrome,and heart failure to alter autonomic reflexes to detrimental effect.