Pancreatic K_Ca3.1 channels in health and disease

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.

Intracellular acidity impedes KCa3.1 activation by Riluzole and SKA-31

“…Considering that in the acidic TME, the cytosolic pH is also acidic ( Navarro et al, 2022 ) the benefits of KCa3.1 positive modulators can be compromised by the loss-of-potency phenotype at acidic pH i described in this study. On the other hand, several cancer types such as glioblastoma ( Brown et al, 2017 ), pancreatic ductal adenocarcinoma ( Soret et al, 2023 ), prostate cancer ( Ohya et al, 2009 ), non-small cell lung cancer ( Bulk et al, 2015 ) and breast cancer ( Gross et al, 2022 ) overexpress KCa3.1. In these cases, the use of an activator would be potentially counterproductive and the loss of the potency of the activators in the acidic TME may be beneficial.…”