Pancreatic Islet Expression and Function of Two-Pore Domain Potassium Channels
The primary channel responsible for glucose induced depolarization of the β-cell is the inward rectifier K+ channel complex (KATP), which b inds the metabolite ATP, reducing its conductance of K+ and causes an increase in the β-cell membrane voltage. Thus, mutations in the KCNJ11 gene, which encodes the pore forming subunit of the KATP channel, which reduce its sensitivity to ATP, have been shown to cause neonatal diabetes. Neonates with diabetes caused by mutations in KATP do, however, have glucose stimulated insulin secretion (GSIS) in the presence of inhibitors of the KATP channel. This is also observed in rodent islets without KATP channels that show GSIS. Thus KATP independent glucose responsive mechanisms play an important role during GSIS.
K2P channels allow K+ flux near the resting membrane potential of β-cells, which will influence GSIS. K2P channels are highly expressed in the pancreatic β-cell and it is thus important to understand how these channels are regulated in the islet as their activity will modulate hormone secretion. The project sets out to identify a glucose and anesthesia sensitive K2P channels of pancreatic islet cells and how these channels regulate islet electrical activity and hormone secretion. Results from this research will provide important insights into how anesthesia affects blood glucose and may identify new therapeutic targets for treating diabetes.
Regulation of Islet Electrical Activity and Hormone Secretion by L-type Calcium Channel Phosphorylation
Insulin secretion is imperative to glucose homeostasis and becomes defective in roughly 7% of the population of the United States that develops diabetes (NIDDK national estimates on diabetes in the US, 2005). Calcium ions are essential for normal GSIS and thus their ability to enter the pancreatic β-cell helps to regulate insulin secretion. Therefore, CaV1.2 and CaV1.3, the main channels that regulate the entry of Ca2+ into the β-cell provide a sensor for modulation of insulin secretion. However, the exact molecular mechanisms that regulate these channels during secretagogue stimulation of the islet are unresolved. Glucose stimulation of islets activates CAM kinase II and this kinase has been shown to regulate cardiac CaV channel activity. Therefore, this project will address dynamic regulation of human and rodent β-cell and a-cell Ca2+ channels by CAM Kinase II and how this influences islet electrical activity, Ca2+ entry, and resulting hormone secretion. The project will identify secretagogue regulated motifs of β-cell CaV channels that will facilitate a greater understanding of the molecular mechanisms regulating islet hormone secretion. This information will also help identify new therapeutic targets for diabetes.
Future Meetings that this research will be presented at: