Insulin levels are inadequate to maintain euglycemia in patients with type-2 diabetes mellitus (T2DM) and in animal models of the disease, which is due in part to perturbations in ?-cell Ca2+ homeostasis. TALK-1 chan- nels are key regulators of pancreatic ?-cell electrical excitability, Ca2+ handling and glucose-stimulated insulin secretion (GSIS). KCNK16 the gene that codes for TALK-1 is the most abundant K+ channel transcript of the ?-cell and TALK-1 is the most islet-restricted ion channel. Moreover, a mutation in KCNK16 results in neonatal diabetes and a nonsynonymous polymorphism in KCNK16 causes a predisposition for developing T2DM. However, our ability to utilize TALK-1 as a therapeutic target to normalize ?-cell Ca2+ homeostasis in T2DM has not been determined. The long term goal of this research is to determine the therapeutic potential of targeting TALK-1 for treating diabetes. The objective of this project is to identify how TALK-1 influence ?-cell Ca2+ han- dling, insulin secretion and glucose homeostasis. This project will test the central hypothesis that TALK-1 inhi- bition normalizes ?-cell Ca2+ homeostasis under diabetic conditions preventing ?-cell dysfunction and maintain- ing euglycemia. This project is supported by strong preliminary data that has identified TALK-1 an important determinant of human and rodent ?-cell ER Ca2+ handling and insulin secretion. Further data that has opti- mized a thallium (Tl+) based fluorescent assay for a high throughput screen (HTS) of human TALK-1 to identify small-molecule probes of this channel; pitot screens (3248 small molecules) also identified the first pharmacol- gocial probes of TALK-1 activity. The rationale that underlies this project is that understanding how ?-cell func- tion is influenced by TALK-1 channel activity with genetic and small-molecule probes will expose novel thera- peutic targets for treating T2DM. This project will be accomplished with the following two specific aims: 1)De- velop potent and selective small-molecule probes of TALK-1 channels; and 2) Determine the therapeutic po- tential of targeting ?-cell TALK-1 channels for treating diabetes. Under the first aim, small-molecule probes of TALK-1 will be identified with a Tl+ assay based HTS of human TALK-1.
This aim will utilize iterative parallel synthesis and verification approaches, to optimize TALK-1 small-molecule probes; testing selectivity (with TALK-1 knockout mouse ?-cells), potency, toxicity and drug metabolism pharmacokinetic (DMPK) profiles with assays such as Tl+ flux, Ca2+ flux, cytotoxicity and tier one in vitro DMPK. Under the second aim, conditionally ablating, blocking or pharmacologically modulating TALK-1 channels in mouse and human ?-cells will be uti- lized to determine how these channels influence ER Ca2+ stores, cytoplasmic Ca2+ homeostasis, membrane potential, GSIS, and glucose homeostasis. The roles of ?-cell TALK-1 will be assessed under physiological conditions as well as under the stressful conditions associated with diabetes both in vivo and in vitro. This pro- ject is significant because it is expected to lead to pharmacological strategies for treating diabetes; it is essen- tial for uncovering novel ?-cell selective therapies for normalizing ER Ca2+ homeostasis in diabetic conditions.

Public Health Relevance

The discovery of how TALK-1 channels control ?-cell function under physiological and diabetic conditions will determine the therapeutic applicability of targeting this islet-restricted ion channel for treating diabetes; thus, the proposed research will provide fundamental knowledge about diabetes that is relevant to public health. Results from this project are also expected to provide significant insights about using small-molecule probes of TALK-1 channels as therapies for treating diabetes. Thus, the proposed research is relevant to NIH?s mission that pertains to developing fundamental knowledge that will help reduce the burdens of human illness.

National Institute of Health (NIH)
National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK)
Research Project (R01)
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Special Emphasis Panel (ZRG1)
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Sato, Sheryl M
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Vanderbilt University Medical Center
Schools of Medicine
United States
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