Pancreatic K_Ca3.1 channels in health and disease

Ion channels play an important role for regulation of the exocrine and the endocrine pancreas. This review focuses on the Ca²⁺-regulated K⁺ channel K_Ca3.1, encoded by the KCNN4 gene, which is present in both parts of the pancreas. In the islets of Langerhans, K_Ca3.1 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 K_Ca3.1 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 K_Ca3.1. For pharmacological targeting of K_Ca3.1 channels, we are discussing the possible benefits K_Ca3.1 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 K_Ca3.1 blocker senicapoc as a tool to monitor channel distribution in pancreatic tissue. In summary, modulating K_Ca3.1 channel activity is a useful strategy for exo-and endocrine pancreatic disease but further studies are needed to evaluate its clinical suitability.