Purinergic Receptors Stimulate Na⁺/Ca^2+ Exchange in Pancreatic Duct Cells: Possible Role of Proteins Handling and Transporting Ca^2+

Abstract

Most purinergic receptors activate intracellular Ca²⁺ signalling, and in epithelia they stimulate transport of major ions. Aim of the present study on pancreatic ducts was to find whether P2 receptors also regulate cellular Ca²⁺ transport, such as that via the Na⁺/Ca²⁺ exchanger (NCX). Since NCX can also be connected with epithelial Ca²⁺ transport, we also investigated expression of some Ca²⁺-handling/transporting proteins. Expression analysis revealed that pancreatic ducts of rat and human duct cell line CFPAC-1 (also PANC-1 and Capan-1) express the Na⁺/Ca²⁺ exchanger (splice variants NCX1.3 and 1.7), as well as the Ca²⁺-sensing receptor and the Ca²⁺-binding protein calbindin-D 9k. These proteins localize to the luminal and lateral membranes of pancreatic duct epithelia. Ca²⁺ imaging experiments showed that activation of purinergic P2Y and P2X receptors stimulated NCX in human and rat duct cells. Application of ATP to CFPAC-1 monolayers also stimulated Ca²⁺ transport from the luminal to the basolateral side. Taken together, these results show that pancreatic ducts express a number of Ca²⁺-handling/transporting proteins and we propose that these together with purinergic receptors play a role in regulation of duct lumen Ca²⁺ content.

Molecular mechanisms underlying Ca2+-mediated motility of human pancreatic duct cells

“…We have shown that NCX1 protein is expressed in BxPc3 cells, which is consistent with a study by Hansen et al (22) showing NCX1 expression in other human pancreatic cancer cell lines (CFPAC-1, PANC-1, and Capan-1). Although TRPC3 is suggested to play a role in the pathogenesis of acute pancreatitis (32), its role in the pathogenesis of pancreatic cancer is not explored.…”

“…1, B and C). Thus our data indicate that both NCX1 and specific TRPC channels are expressed in human pancreatic cancer cells (22).…”

“…Although NCX expression and function have been demonstrated in intestinal epithelial cells (12) and in pancreatic ␤-islet cells (12), little is known about NCX in human pancreatic adenocarcinoma cells (22). Here, we demonstrated that both the mRNA transcript and protein of NCX1 are expressed in pancreatic cancer cells (Fig.…”

“…Two subfamilies have been described in mammalian cells: one in which Ca 2ϩ movement is dependent only on Na ϩ (NCX1-3) and the other in which Ca 2ϩ transport is also dependent on K ϩ (NCKX1-6). TRPC and NCX have been described in mammalian tissues for decades, but very little is known about the expression and function of these proteins in human pancreatic cancer cells (4,22,32). Although the role of TRP channels has been reported in colorectal, colon, thyroid, breast, ovarian, and prostate cancer (7,64), the involvement of TRP channels and NCX in pancreatic cancer development is currently unexplored.…”

Glycolytic ATP Fuels the Plasma Membrane Calcium Pump Critical for Pancreatic Cancer Cell Survival

“…Furthermore, NCX is reported to be expressed in human PDAC cells (30–32). To determine whether NCX contributed to Ca 2+ clearance in PANC1 and MIA PaCa-2 cells under the conditions of our in situ [Ca 2+ ] i clearance assay, we replaced extracellular Na + with equimolar N -methyl d -glucamine (Na + -free/NMDG).…”