Pancreatic KCa3.1 channels in health and disease

Soret, Benjamin; Hense, Jurek; Lüdtke, Simon; Thale, Insa; Schwab, Albrecht; Düfer, Martina

Abstract

Ion channels play an important role for regulation of the exocrine and the endocrine pancreas. This review focuses on the Ca2+-regulated K+ channel KCa3.1, encoded by the KCNN4 gene, which is present in both parts of the pancreas. In the islets of Langerhans, KCa3.1 channels are involved in the regulation of membrane potential oscillations characterizing nutrient-stimulated islet activity. Channel upregulation is induced by gluco- or lipotoxic conditions and might contribute to micro-inflammation and impaired insulin release in type 2 diabetes mellitus as well as to diabetes-associated renal and vascular complications. In the exocrine pancreas KCa3.1 channels are expressed in acinar and ductal cells. They are thought to play a role for anion secretion during digestion but their physiological role has not been fully elucidated yet. Pancreatic carcinoma, especially pancreatic ductal adenocarcinoma (PDAC), is associated with drastic overexpression of KCa3.1. For pharmacological targeting of KCa3.1 channels, we are discussing the possible benefits KCa3.1 channel inhibitors might provide in the context of diabetes mellitus and pancreatic cancer, respectively. We are also giving a perspective for the use of a fluorescently labeled derivative of the KCa3.1 blocker senicapoc as a tool to monitor channel distribution in pancreatic tissue. In summary, modulating KCa3.1 channel activity is a useful strategy for exo-and endocrine pancreatic disease but further studies are needed to evaluate its clinical suitability.