Pancreatic function is central to Metabolic Syndrome (MS) and patients exhibit long-term hyperinsulinemia as the pancreas compensates for nutrient overload through insulin over-production. Beta cell exhaustion, insulin resistance and diabetes follow this chronic hyperinsulinemia. Transient Receptor Potential (TRP) cation channels are druggable targets in several sequelae of the MS (e.g., cardiovascular disease), and TRPA1 has recently been directly implicated in the pancreatic dysfunction underlying MS. Recent studies show that TRPA1 conducts Ca2+ to controls insulin release in the pancreas, offering TRPA1 as a therapeutic target for regulation of insulin output. TRPA1 is best understood as nocioceptive channel. An intriguing human heritable mutation in TRPA1 (OMIM: 615040) causes serious episodic pain in response to fasting, establishing another link between TRPA1 and metabolism. However, significant knowledge gaps remain concerning (1) the mechanistic basis for coupling of metabolic/endocrine inputs to TRPA1 activity, and (2) whether pharmacological regulation of TRPA1 translates to modulation of metabolic pathways in whole organisms. Our new preliminary data validate expression of TRPA1 in the pancreas, and other tissues, and directly link TRPA1 to metabolism and mitochondria. Three independent techniques (EM, IF and subcellular fractionation) show that TRPA1 localizes to mitochondria (Mt). Moreover, we demonstrate interactions between endogenous TRPA1 and all isoenzymes of creatine kinase (CK), plus pyruvate dehydrogenase (PDH) subunits. Strikingly, the former inhibit TRPA1 channel activity, indicating that TRPA1 is regulated by metabolic enzymes. These findings suggest TRPA1 transduces the effects of its activators (temperature, Ca2+, O2, and pungent compounds) into metabolic pathways, linking directly to mitochondrial processes and status. These findings raise new questions that will be addressed in three Specific Aims, enabled by a comprehensive set of TRPA1 modulators, antibodies, and in vivo knockout and gene editing tools available in the PI's laboratory. These questions are: What is the mechanistic basis for coupling of pancreatic beta cell function to TRPA1 activity, does this critically involve Creatine Kinase or PDH? (Aim 1); Where does this regulation and functional contribution to beta cell function reside, in the plasma membrane, mitochondria, and in other tissues than the pancreas? (Aim 2); and Does pharmacological regulation of TRPA1 translate to modulation of metabolic pathways and disease outcomes at the whole organism level? (Aim 3).

National Institute of Health (NIH)
National Institute of General Medical Sciences (NIGMS)
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University of Hawaii
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