Protein kinase A and regulation of neonatal Nav1.5 expression in human breast cancer cells: Activity-dependent positive feedback and cellular migration |
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| Authors: | Athina-Myrto Chioni Dongmin Shao Richard Grose Mustafa B.A. Djamgoz |
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| Affiliation: | 1. Department of Clinical Pharmacology, Niigata University of Pharmacy and Applied Life Sciences, Niigata 956 8603, Japan;2. Department of Cardiovascular Sciences, Houston Methodist Research Center, Houston 77087, TX, USA;3. J.K.K. Nattraja College of Pharmacy, Natarajapuram, Komarapalayam 638183, Namakkal District, Tamil Nadu, India;4. Department of Cardiology, Yamanashi Prefectural Central Hospital, 1-1-1 Fujimi, Kofu, Yamanashi 400 8506, Japan;5. Department of Gastroenterology, Niigata University Graduate School of Medical and Dental Sciences, Niigata 951 8510, Japan;6. Department of Pharmacology, College of Pharmacy, King Khalid University, Abha, Saudi Arabia;1. Department of Cardiovascular Medicine, the Second Affiliated Hospital of Nanchang University, Nanchang, Jiangxi, 330006, China;2. Jiangxi Key Laboratory of Molecular Medicine, Nanchang, Jiangxi 330006, China;3. Department of General Surgery, the Second Affiliated Hospital of Nanchang University, Nanchang, Jiangxi 330006, China;4. Department of Nephrology, the Second Affiliated Hospital of Nanchang University, Nanchang, Jiangxi 330006, China;1. Department of Medicine, Division of Cardiovascular Medicine, University of Wisconsin, Madison, WI 53792, USA;2. School of Business and Applied Arts, Division of Visual Communication, Madison College, Madison, WI 53704, USA |
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| Abstract: | Voltage-gated Na+ channels (VGSCs) are expressed in excitable cells (e.g. neurons and muscles), as well as in some classically ‘non-excitable’ cells (e.g. fibroblasts), and in carcinomas. In general, functional expression of VGSCs in plasma membrane (PM) is hierarchical and dynamic. Previously, we have shown that an activity-dependent positive feedback mechanism involving cAMP-dependent protein kinase A (PKA) plays a significant role in upregulation of VGSCs in strongly metastatic rat prostate cancer Mat-LyLu cells expressing Nav1.7. Here, we investigated the possible role of PKA in VGSC regulation and its functional consequences in strongly metastatic human breast cancer (BCa) MDA-MB-231 cells, where the neonatal splice form of Nav1.5 (nNav1.5) is the predominant VGSC present. Treatment with the PKA activator forskolin for 24 h increased mRNA and PM protein levels of nNav1.5, without changing the total VGSC protein level. Opposite effects were obtained by application of the PKA inhibitor KT5720 or the highly specific VGSC blocker tetrodotoxin (TTX), the latter implying activity-dependent upregulation. We tested the possibility, therefore, that the activity dependence of VGSC (nNav1.5) expression involved PKA. Indeed, TTX pretreatment reduced the level of phosphorylated PKA and eliminated basal and PKA-stimulated cellular migration. These data suggested that activity-dependent positive feedback mediated by PKA plays an important role in the functional expression of nNav1.5 in BCa, and in turn, this enhances the cells’ metastatic potential. |
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