{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2025,10,12]],"date-time":"2025-10-12T04:31:39Z","timestamp":1760243499312,"version":"build-2065373602"},"reference-count":81,"publisher":"MDPI AG","issue":"11","license":[{"start":{"date-parts":[[2022,10,27]],"date-time":"2022-10-27T00:00:00Z","timestamp":1666828800000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"name":"National Institutes of Health","award":["HL076125","HL141473","HL066299","HL160988","BOYD22H0","FIEDLE22H0"],"award-info":[{"award-number":["HL076125","HL141473","HL066299","HL160988","BOYD22H0","FIEDLE22H0"]}]},{"name":"Cystic Fibrosis Foundation","award":["HL076125","HL141473","HL066299","HL160988","BOYD22H0","FIEDLE22H0"],"award-info":[{"award-number":["HL076125","HL141473","HL066299","HL160988","BOYD22H0","FIEDLE22H0"]}]},{"name":"University of South Alabama Office of Research and Economic Development","award":["HL076125","HL141473","HL066299","HL160988","BOYD22H0","FIEDLE22H0"],"award-info":[{"award-number":["HL076125","HL141473","HL066299","HL160988","BOYD22H0","FIEDLE22H0"]}]},{"name":"Whiddon College of Medicine at the University of South Alabama","award":["HL076125","HL141473","HL066299","HL160988","BOYD22H0","FIEDLE22H0"],"award-info":[{"award-number":["HL076125","HL141473","HL066299","HL160988","BOYD22H0","FIEDLE22H0"]}]}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["Biology"],"abstract":"<jats:p>The analysis of blood samples from mice treated with the PDE4 inhibitor Roflumilast revealed an unexpected reduction in serum potassium levels, while sodium and chloride levels were unaffected. Treatment with several structurally distinct PAN-PDE4 inhibitors, including Roflumilast, Rolipram, RS25344, and YM976 dose-dependently reduced serum potassium levels, indicating the effect is a class-characteristic property. PDE4 inhibition also induces hypothermia and hypokinesia in mice. However, while general anesthesia abrogates these effects of PDE4 inhibitors, potassium levels decrease to similar extents in both awake as well as in fully anesthetized mice. This suggests that the hypokalemic effects of PDE4 inhibitors occur independently of hypothermia and hypokinesia. PDE4 inhibition reduces serum potassium within 15 min of treatment, consistent with a rapid transcellular shift of potassium. Catecholamines promote the uptake of potassium into the cell via increased cAMP signaling. PDE4 appears to modulate these adrenoceptor-mediated effects, as PDE4 inhibition has no additional effects on serum potassium in the presence of saturating doses of the \u03b2-adrenoceptor agonist Isoprenaline or the \u03b12-blocker Yohimbine, and is partially blocked by pre-treatment with the \u03b2-blocker Propranolol. Together, these data suggest that PDE4 inhibitors reduce serum potassium levels by modulating the adrenergic regulation of cellular potassium uptake.<\/jats:p>","DOI":"10.3390\/biology11111582","type":"journal-article","created":{"date-parts":[[2022,10,27]],"date-time":"2022-10-27T20:37:58Z","timestamp":1666903078000},"page":"1582","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":0,"title":["Non-Selective PDE4 Inhibition Induces a Rapid and Transient Decrease of Serum Potassium in Mice"],"prefix":"10.3390","volume":"11","author":[{"given":"Abigail","family":"Boyd","sequence":"first","affiliation":[{"name":"Department of Biochemistry & Molecular Biology, College of Medicine, University of South Alabama, Mobile, AL 36688, USA"},{"name":"Center for Lung Biology, College of Medicine, University of South Alabama, Mobile, AL 36688, USA"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Peter","family":"Lochmaier","sequence":"additional","affiliation":[{"name":"Department of Biochemistry & Molecular Biology, College of Medicine, University of South Alabama, Mobile, AL 36688, USA"},{"name":"Center for Lung Biology, College of Medicine, University of South Alabama, Mobile, AL 36688, USA"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-0062-7359","authenticated-orcid":false,"given":"Daniel","family":"Irelan","sequence":"additional","affiliation":[{"name":"Department of Biochemistry & Molecular Biology, College of Medicine, University of South Alabama, Mobile, AL 36688, USA"},{"name":"Center for Lung Biology, College of Medicine, University of South Alabama, Mobile, AL 36688, USA"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Edward","family":"Fiedler","sequence":"additional","affiliation":[{"name":"Department of Biochemistry & Molecular Biology, College of Medicine, University of South Alabama, Mobile, AL 36688, USA"},{"name":"Center for Lung Biology, College of Medicine, University of South Alabama, Mobile, AL 36688, USA"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Ji","family":"Lee","sequence":"additional","affiliation":[{"name":"Center for Lung Biology, College of Medicine, University of South Alabama, Mobile, AL 36688, USA"},{"name":"Department of Internal Medicine, College of Medicine, University of South Alabama, Mobile, AL 36688, USA"},{"name":"Division of Pulmonary and Critical Care Medicine, College of Medicine, University of South Alabama, Mobile, AL 36688, USA"},{"name":"Department of Physiology and Cell Biology, College of Medicine, University of South Alabama, Mobile, AL 36688, USA"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Brian","family":"Fouty","sequence":"additional","affiliation":[{"name":"Center for Lung Biology, College of Medicine, University of South Alabama, Mobile, AL 36688, USA"},{"name":"Department of Internal Medicine, College of Medicine, University of South Alabama, Mobile, AL 36688, USA"},{"name":"Division of Pulmonary and Critical Care Medicine, College of Medicine, University of South Alabama, Mobile, AL 36688, USA"},{"name":"Department of Pharmacology, College of Medicine, University of South Alabama, Mobile, AL 36688, USA"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Lina","family":"Abou Saleh","sequence":"additional","affiliation":[{"name":"Department of Biochemistry & Molecular Biology, College of Medicine, University of South Alabama, Mobile, AL 36688, USA"},{"name":"Center for Lung Biology, College of Medicine, University of South Alabama, Mobile, AL 36688, USA"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-5588-9060","authenticated-orcid":false,"given":"Wito","family":"Richter","sequence":"additional","affiliation":[{"name":"Department of Biochemistry & Molecular Biology, College of Medicine, University of South Alabama, Mobile, AL 36688, USA"},{"name":"Center for Lung Biology, College of Medicine, University of South Alabama, Mobile, AL 36688, USA"}],"role":[{"role":"author","vocabulary":"crossref"}]}],"member":"1968","published-online":{"date-parts":[[2022,10,27]]},"reference":[{"key":"ref_1","doi-asserted-by":"crossref","first-page":"595","DOI":"10.1111\/j.1472-8206.2010.00859.x","article-title":"Hormonal pharmacological modification of plasma potassium homeostasis","volume":"24","author":"Clausen","year":"2010","journal-title":"Fundam. Clin. Pharmacol."},{"key":"ref_2","doi-asserted-by":"crossref","first-page":"480","DOI":"10.1152\/advan.00121.2016","article-title":"Physiology and pathophysiology of potassium homeostasis","volume":"40","author":"Palmer","year":"2016","journal-title":"Adv. Physiol. Educ."},{"key":"ref_3","doi-asserted-by":"crossref","first-page":"1050","DOI":"10.2215\/CJN.08580813","article-title":"Regulation of Potassium Homeostasis","volume":"10","author":"Palmer","year":"2015","journal-title":"Clin. J. Am. Soc. Nephrol."},{"key":"ref_4","doi-asserted-by":"crossref","first-page":"42","DOI":"10.7748\/ns2014.03.28.29.42.e5531","article-title":"Fluid and electrolyte balance","volume":"28","author":"McLafferty","year":"2014","journal-title":"Nurs. Stand."},{"key":"ref_5","first-page":"159","article-title":"The Na+\/K(+)-pump protects muscle excitability and contractility during exercise","volume":"28","author":"Nielsen","year":"2000","journal-title":"Exerc. Sport Sci. Rev."},{"key":"ref_6","doi-asserted-by":"crossref","first-page":"1019","DOI":"10.1002\/jnr.23499","article-title":"Roles of astrocytic Na(+),K(+)-ATPase and glycogenolysis for K(+) homeostasis in mammalian brain","volume":"93","author":"Hertz","year":"2015","journal-title":"J. Neurosci. Res."},{"key":"ref_7","doi-asserted-by":"crossref","first-page":"825","DOI":"10.1113\/jphysiol.2007.135673","article-title":"Skeletal muscle vasodilatation at the onset of exercise","volume":"583","author":"Clifford","year":"2007","journal-title":"J. Physiol."},{"key":"ref_8","doi-asserted-by":"crossref","first-page":"288","DOI":"10.1152\/japplphysiol.01037.2007","article-title":"Muscle K+, Na+, and Cl disturbances and Na+-K+ pump inactivation: Implications for fatigue","volume":"104","author":"McKenna","year":"2008","journal-title":"J. Appl. Physiol."},{"key":"ref_9","doi-asserted-by":"crossref","first-page":"1513","DOI":"10.2215\/CJN.04540511","article-title":"A critically swift response: Insulin-stimulated potassium and glucose transport in skeletal muscle","volume":"6","author":"Ho","year":"2011","journal-title":"Clin. J. Am. Soc. Nephrol."},{"key":"ref_10","doi-asserted-by":"crossref","first-page":"E1","DOI":"10.1152\/ajpendo.00539.2015","article-title":"Na,K-ATPase regulation in skeletal muscle","volume":"311","author":"Pirkmajer","year":"2016","journal-title":"Am. J. Physiol. Endocrinol. Metab."},{"key":"ref_11","doi-asserted-by":"crossref","first-page":"869","DOI":"10.1038\/ki.1990.284","article-title":"Albuterol and insulin for treatment of hyperkalemia in hemodialysis patients","volume":"38","author":"Allon","year":"1990","journal-title":"Kidney Int."},{"key":"ref_12","doi-asserted-by":"crossref","first-page":"162","DOI":"10.1111\/j.1365-2362.1988.tb02407.x","article-title":"Decrease of plasma potassium due to inhalation of beta-2-agonists: Absence of an additional effect of intravenous theophylline","volume":"18","author":"Deenstra","year":"1988","journal-title":"Eur. J. Clin. Investig."},{"key":"ref_13","doi-asserted-by":"crossref","first-page":"713","DOI":"10.1001\/archinte.1987.00370040095017","article-title":"Potassium-lowering effect of albuterol for hyperkalemia in renal failure","volume":"147","author":"Montoliu","year":"1987","journal-title":"Arch. Intern. Med."},{"key":"ref_14","doi-asserted-by":"crossref","first-page":"33","DOI":"10.1159\/000065375","article-title":"Therapeutic approach to hyperkalemia","volume":"92","author":"Kim","year":"2002","journal-title":"Nephron"},{"key":"ref_15","doi-asserted-by":"crossref","first-page":"770","DOI":"10.1038\/s41573-019-0033-4","article-title":"Therapeutic targeting of 3\u2032,5\u2032-cyclic nucleotide phosphodiesterases: Inhibition and beyond","volume":"18","author":"Baillie","year":"2019","journal-title":"Nat. Rev. Drug Dis."},{"key":"ref_16","doi-asserted-by":"crossref","first-page":"481","DOI":"10.1146\/annurev.biochem.76.060305.150444","article-title":"Biochemistry and physiology of cyclic nucleotide phosphodiesterases: Essential components in cyclic nucleotide signaling","volume":"76","author":"Conti","year":"2007","journal-title":"Annu. Rev. Biochem."},{"key":"ref_17","doi-asserted-by":"crossref","first-page":"366","DOI":"10.1016\/j.pharmthera.2005.07.003","article-title":"Cyclic nucleotide phosphodiesterase (PDE) superfamily: A new target for the development of specific therapeutic agents","volume":"109","author":"Lugnier","year":"2006","journal-title":"Pharmacol. Ther."},{"key":"ref_18","doi-asserted-by":"crossref","first-page":"5493","DOI":"10.1074\/jbc.R200029200","article-title":"Cyclic AMP-specific PDE4 phosphodiesterases as critical components of cyclic AMP signaling","volume":"278","author":"Conti","year":"2003","journal-title":"J. Biol. Chem."},{"key":"ref_19","doi-asserted-by":"crossref","first-page":"1016","DOI":"10.1124\/pharmrev.120.000273","article-title":"The Molecular Biology of Phosphodiesterase 4 Enzymes as Pharmacological Targets: An Interplay of Isoforms, Conformational States, and Inhibitors","volume":"73","author":"Paes","year":"2021","journal-title":"Pharmacol. Rev."},{"key":"ref_20","doi-asserted-by":"crossref","unstructured":"Beavo, J.A., Francis, S.H., and Houslay, M.D. (2007). Cyclic Nucleotide Phosphodiesterases in Health and Disease, CRC Press.","DOI":"10.1201\/9781420020847.ch1"},{"key":"ref_21","doi-asserted-by":"crossref","first-page":"1503","DOI":"10.1016\/S1359-6446(05)03622-6","article-title":"Keynote review: Phosphodiesterase-4 as a therapeutic target","volume":"10","author":"Houslay","year":"2005","journal-title":"Drug Discov. Today"},{"key":"ref_22","first-page":"e21797","article-title":"Ablation of PDE4B protects from Pseudomonas aeruginosa-induced acute lung injury in mice by ameliorating the cytostorm and associated hypothermia","volume":"35","author":"Boyd","year":"2021","journal-title":"FASEB J. Off. Publ. Fed. Am. Soc. Exp. Biol."},{"key":"ref_23","doi-asserted-by":"crossref","first-page":"7628","DOI":"10.1073\/pnas.122041599","article-title":"Induction of the cyclic nucleotide phosphodiesterase PDE4B is essential for LPS-activated TNF-alpha responses","volume":"99","author":"Jin","year":"2002","journal-title":"Proc. Natl. Acad. Sci. USA"},{"key":"ref_24","first-page":"197","article-title":"Phosphodiesterase 4 and its inhibitors in inflammatory diseases","volume":"35","author":"Jin","year":"2012","journal-title":"Chang. Gung. Med. J."},{"key":"ref_25","doi-asserted-by":"crossref","first-page":"1958","DOI":"10.1002\/hep.30761","article-title":"Phosphodiesterase 4 Inhibition as a Therapeutic Target for Alcoholic Liver Disease: From Bedside to Bench","volume":"70","author":"Rodriguez","year":"2019","journal-title":"Hepatology"},{"key":"ref_26","doi-asserted-by":"crossref","first-page":"1011","DOI":"10.1517\/14728222.2013.818656","article-title":"PDE4 as a target for cognition enhancement","volume":"17","author":"Richter","year":"2013","journal-title":"Expert Opin. Targets"},{"key":"ref_27","doi-asserted-by":"crossref","first-page":"419","DOI":"10.1007\/s00213-008-1273-x","article-title":"Selective phosphodiesterase inhibitors: A promising target for cognition enhancement","volume":"202","author":"Reneerkens","year":"2009","journal-title":"Psychopharmacology"},{"key":"ref_28","doi-asserted-by":"crossref","unstructured":"Kamel, R., Leroy, J., Vandecasteele, G., and Fischmeister, R. (2022). Cyclic nucleotide phosphodiesterases as therapeutic targets in cardiac hypertrophy and heart failure. Nat. Rev. Cardiol., (In English).","DOI":"10.1038\/s41569-022-00756-z"},{"key":"ref_29","doi-asserted-by":"crossref","first-page":"950","DOI":"10.1161\/01.RES.0000261934.56938.38","article-title":"cAMP-Specific phosphodiesterase-4 enzymes in the cardiovascular system: A molecular toolbox for generating compartmentalized cAMP signaling","volume":"100","author":"Houslay","year":"2007","journal-title":"Circ. Res."},{"key":"ref_30","doi-asserted-by":"crossref","first-page":"429","DOI":"10.1111\/obr.12385","article-title":"Phosphodiesterase-4 inhibition as a therapeutic strategy for metabolic disorders","volume":"17","author":"Wu","year":"2016","journal-title":"Obes. Rev. Off. J. Int. Assoc. Study Obes."},{"key":"ref_31","doi-asserted-by":"crossref","first-page":"1891","DOI":"10.1042\/BCJ20210212","article-title":"The cAMP-phosphodiesterase 4 (PDE4) controls \u03b2-adrenoceptor- and CFTR-dependent saliva secretion in mice","volume":"478","author":"Boyd","year":"2021","journal-title":"Biochem. J."},{"key":"ref_32","doi-asserted-by":"crossref","unstructured":"Boyd, A., Aragon, I.V., Rich, J., McDonough, W., Oditt, M., Irelan, D., Fiedler, E., Abou Saleh, L., and Richter, W. (2021). Assessment of PDE4 Inhibitor-Induced Hypothermia as a Correlate of Nausea in Mice. Biology, 10.","DOI":"10.3390\/biology10121355"},{"key":"ref_33","first-page":"12533","article-title":"PAN-selective inhibition of cAMP-phosphodiesterase 4 (PDE4) induces gastroparesis in mice","volume":"34","author":"McDonough","year":"2020","journal-title":"FASEB J. Off. Publ. Fed. Am. Soc. Exp. Biol."},{"key":"ref_34","doi-asserted-by":"crossref","first-page":"114158","DOI":"10.1016\/j.bcp.2020.114158","article-title":"Inhibition of type 4 cAMP-phosphodiesterases (PDE4s) in mice induces hypothermia via effects on behavioral and central autonomous thermoregulation","volume":"180","author":"McDonough","year":"2020","journal-title":"Biochem. Pharmacol."},{"key":"ref_35","doi-asserted-by":"crossref","first-page":"13","DOI":"10.1016\/0163-7258(91)90039-O","article-title":"Cyclic nucleotide phosphodiesterases: Pharmacology, biochemistry and function","volume":"51","author":"Thompson","year":"1991","journal-title":"Pharmacol. Ther."},{"key":"ref_36","first-page":"147","article-title":"Roflumilast: First phosphodiesterase 4 inhibitor approved for treatment of COPD","volume":"4","author":"Giembycz","year":"2010","journal-title":"Drug Des. Devel."},{"key":"ref_37","doi-asserted-by":"crossref","first-page":"235","DOI":"10.1016\/j.pupt.2010.03.011","article-title":"The preclinical pharmacology of roflumilast\u2014A selective, oral phosphodiesterase 4 inhibitor in development for chronic obstructive pulmonary disease","volume":"23","author":"Hatzelmann","year":"2010","journal-title":"Pulm. Pharmacol. Ther."},{"key":"ref_38","first-page":"1142","article-title":"Studies on mechanisms of low emetogenicity of YM976, a novel phosphodiesterase type 4 inhibitor","volume":"298","author":"Aoki","year":"2001","journal-title":"J. Pharm. Exp."},{"key":"ref_39","doi-asserted-by":"crossref","first-page":"57","DOI":"10.1016\/S0014-2999(03)01754-0","article-title":"Relaxant effect of YM976, a novel phosphodiesterase 4 inhibitor, on bovine tracheal smooth muscle","volume":"470","author":"Moriuchi","year":"2003","journal-title":"Eur. J. Pharm."},{"key":"ref_40","doi-asserted-by":"crossref","first-page":"114477","DOI":"10.1016\/j.bcp.2021.114477","article-title":"Inhibition of cAMP-phosphodiesterase 4 (PDE4) potentiates the anesthetic effects of Isoflurane in mice","volume":"186","author":"Aragon","year":"2021","journal-title":"Biochem. Pharmacol."},{"key":"ref_41","doi-asserted-by":"crossref","first-page":"35","DOI":"10.1016\/j.resuscitation.2017.07.003","article-title":"The impact of hypothermia on serum potassium concentration: A systematic review","volume":"118","author":"Buse","year":"2017","journal-title":"Resuscitation"},{"key":"ref_42","doi-asserted-by":"crossref","first-page":"275","DOI":"10.1007\/BF01691254","article-title":"Serum potassium levels during prolonged hypothermia","volume":"9","author":"Koht","year":"1983","journal-title":"Intensive Care Med."},{"key":"ref_43","doi-asserted-by":"crossref","first-page":"1545","DOI":"10.1097\/00003246-199112000-00018","article-title":"Effects of acute hypothermia and beta-adrenergic receptor blockade on serum potassium concentration in rats","volume":"19","author":"Sprung","year":"1991","journal-title":"Crit. Care Med."},{"key":"ref_44","first-page":"S69","article-title":"Potassium correction of hypothermic hypokalemia induces hyperkalemia after rewarming","volume":"37","author":"Sprung","year":"1990","journal-title":"Can. J. Anaesth."},{"key":"ref_45","doi-asserted-by":"crossref","first-page":"107","DOI":"10.7150\/ijms.2.107","article-title":"Potassium Deposition during and after Hypokinesia in Potassium Supplemented and Unsupplemented Rats","volume":"2","author":"Zorbas","year":"2005","journal-title":"Int. J. Med. Sci."},{"key":"ref_46","doi-asserted-by":"crossref","first-page":"668","DOI":"10.1007\/s12011-010-8900-1","article-title":"Muscle Potassium and Potassium Losses during Hypokinesia in Healthy Subjects","volume":"143","author":"Federenko","year":"2011","journal-title":"Biol. Trace Elem. Res."},{"key":"ref_47","doi-asserted-by":"crossref","first-page":"97","DOI":"10.1053\/jscd.2003.14","article-title":"Prolonged drug-induced hypothermia in experimental stroke","volume":"12","author":"Johansen","year":"2003","journal-title":"J. Stroke Cereb. Dis."},{"key":"ref_48","first-page":"83","article-title":"The Physiologic Effects of Isoflurane, Sevoflurane, and Hypothermia Used for Anesthesia in Neonatal Rats (Rattus norvegicus)","volume":"55","author":"Huss","year":"2016","journal-title":"J. Am. Assoc. Lab. Anim. Sci. JAALAS"},{"key":"ref_49","doi-asserted-by":"crossref","first-page":"1001","DOI":"10.1213\/ANE.0b013e31828842f0","article-title":"The impact of hypothermia on emergence from isoflurane anesthesia in orexin neuron-ablated mice","volume":"116","author":"Kuroki","year":"2013","journal-title":"Anesth. Analg."},{"key":"ref_50","doi-asserted-by":"crossref","first-page":"429","DOI":"10.1097\/00000542-200103000-00011","article-title":"The effect of hypothermia on isoflurane MAC in children","volume":"94","author":"Liu","year":"2001","journal-title":"Anesthesiology"},{"key":"ref_51","doi-asserted-by":"crossref","first-page":"10","DOI":"10.1186\/s12576-021-00794-1","article-title":"Successful induction of deep hypothermia by isoflurane anesthesia and cooling in a non-hibernator, the rat","volume":"71","author":"Shimaoka","year":"2021","journal-title":"J. Physiol. Sci. JPS"},{"key":"ref_52","doi-asserted-by":"crossref","first-page":"624","DOI":"10.1152\/japplphysiol.00680.2017","article-title":"Protection against severe hypokalemia but impaired cardiac repolarization after intense rowing exercise in healthy humans receiving salbutamol","volume":"125","author":"Atanasovska","year":"2018","journal-title":"J. Appl. Physiol."},{"key":"ref_53","doi-asserted-by":"crossref","first-page":"143","DOI":"10.1111\/j.1472-8206.1993.tb00228.x","article-title":"Effects of catecholamines on plasma potassium: The role of alpha- and beta-adrenoceptors","volume":"7","author":"Moratinos","year":"1993","journal-title":"Fundam. Clin. Pharm."},{"key":"ref_54","doi-asserted-by":"crossref","first-page":"1414","DOI":"10.1056\/NEJM198312083092303","article-title":"Hypokalemia from beta2-receptor stimulation by circulating epinephrine","volume":"309","author":"Brown","year":"1983","journal-title":"N. Engl. J. Med."},{"key":"ref_55","doi-asserted-by":"crossref","unstructured":"Beavo, J., Francis, S., and Houslay, M. (2006). Cyclic Nucleotide Phosphodiesterases in Health and Disease, CRC Press.","DOI":"10.1201\/9781420020847.ch1"},{"key":"ref_56","doi-asserted-by":"crossref","first-page":"12791","DOI":"10.1073\/pnas.0805167105","article-title":"EPAC and PKA allow cAMP dual control over DNA-PK nuclear translocation","volume":"105","author":"Huston","year":"2008","journal-title":"Proc. Natl. Acad. Sci. USA"},{"key":"ref_57","first-page":"46","article-title":"Etiology and symptoms of severe hypokalemia in emergency department patients","volume":"21","author":"Marti","year":"2014","journal-title":"Eur. J. Emerg. Med. Off. J. Eur. Soc. Emerg. Med."},{"key":"ref_58","first-page":"487","article-title":"Potassium Disorders: Hypokalemia and Hyperkalemia","volume":"92","author":"Viera","year":"2015","journal-title":"Am. Fam. Physician"},{"key":"ref_59","doi-asserted-by":"crossref","first-page":"R135","DOI":"10.1530\/EC-18-0109","article-title":"Hypokalemia: A clinical update","volume":"7","author":"Kardalas","year":"2018","journal-title":"Endocr. Connect."},{"key":"ref_60","doi-asserted-by":"crossref","first-page":"335","DOI":"10.1016\/j.semnephrol.2005.03.009","article-title":"Role of muscle in regulating extracellular [K+]","volume":"25","author":"McDonough","year":"2005","journal-title":"Semin. Nephrol."},{"key":"ref_61","doi-asserted-by":"crossref","first-page":"101","DOI":"10.1016\/0024-3205(87)90258-X","article-title":"Adrenaline causes potassium influx in skeletal muscle and potassium efflux in cardiac muscle in rats: The role of Na\/K ATPase","volume":"40","author":"Struthers","year":"1987","journal-title":"Life Sci."},{"key":"ref_62","doi-asserted-by":"crossref","unstructured":"Hayoz, S., Cubano, L., Maldonado, H., and Bychkov, R. (2013). Protein kinase A and C regulate leak potassium currents in freshly isolated vascular myocytes from the aorta. PLoS ONE, 8.","DOI":"10.1371\/journal.pone.0075077"},{"key":"ref_63","doi-asserted-by":"crossref","first-page":"273","DOI":"10.1002\/jcp.1041120217","article-title":"Cyclic AMP stimulation of Na-K pump activity in quiescent swiss 3T3 cells","volume":"112","author":"Paris","year":"1982","journal-title":"J. Cell. Physiol."},{"key":"ref_64","doi-asserted-by":"crossref","first-page":"C1363","DOI":"10.1152\/ajpcell.00027.2010","article-title":"Role of phospholemman phosphorylation sites in mediating kinase-dependent regulation of the Na+-K+-ATPase","volume":"299","author":"Han","year":"2010","journal-title":"Am. J. Physiol. Cell Physiol."},{"key":"ref_65","doi-asserted-by":"crossref","first-page":"F241","DOI":"10.1152\/ajprenal.00126.2005","article-title":"FXYD proteins: New regulators of Na-K-ATPase","volume":"290","author":"Geering","year":"2006","journal-title":"Am. J. Physiol. Ren. Physiol."},{"key":"ref_66","doi-asserted-by":"crossref","first-page":"1123","DOI":"10.1161\/CIRCULATIONAHA.119.040557","article-title":"Phospholemman Phosphorylation Regulates Vascular Tone, Blood Pressure, and Hypertension in Mice and Humans","volume":"143","author":"Boguslavskyi","year":"2021","journal-title":"Circulation"},{"key":"ref_67","doi-asserted-by":"crossref","first-page":"3445","DOI":"10.1074\/jbc.M708875200","article-title":"Homeostatic regulation of Kv1.2 potassium channel trafficking by cyclic AMP","volume":"283","author":"Connors","year":"2008","journal-title":"J. Biol. Chem."},{"key":"ref_68","doi-asserted-by":"crossref","first-page":"671","DOI":"10.1016\/S0960-9822(00)00516-9","article-title":"Cyclic AMP regulates the HERG K(+) channel by dual pathways","volume":"10","author":"Cui","year":"2000","journal-title":"Curr. Biol."},{"key":"ref_69","doi-asserted-by":"crossref","first-page":"476","DOI":"10.1074\/jbc.M705830200","article-title":"Phosphorylation of phospholemman (FXYD1) by protein kinases A and C modulates distinct Na,K-ATPase isozymes","volume":"283","author":"Bibert","year":"2008","journal-title":"J. Biol. Chem."},{"key":"ref_70","doi-asserted-by":"crossref","first-page":"72","DOI":"10.1093\/cvr\/cvu182","article-title":"Cardiac hypertrophy in mice expressing unphosphorylatable phospholemman","volume":"104","author":"Boguslavskyi","year":"2014","journal-title":"Cardiovasc. Res."},{"key":"ref_71","doi-asserted-by":"crossref","first-page":"83","DOI":"10.1016\/j.yjmcc.2013.05.002","article-title":"Novel regulation of cardiac Na pump via phospholemman","volume":"61","author":"Pavlovic","year":"2013","journal-title":"J. Mol. Cell. Cardiol."},{"key":"ref_72","doi-asserted-by":"crossref","first-page":"C1346","DOI":"10.1152\/ajpcell.00523.2008","article-title":"FXYD1 phosphorylation in vitro and in adult rat cardiac myocytes: Threonine 69 is a novel substrate for protein kinase C","volume":"296","author":"Fuller","year":"2009","journal-title":"Am. J. Physiol. Cell. Physiol."},{"key":"ref_73","doi-asserted-by":"crossref","first-page":"305","DOI":"10.1111\/j.1474-8673.1991.tb00254.x","article-title":"Role of alpha-adrenoceptors in control of plasma potassium in conscious rabbits","volume":"11","author":"Reverte","year":"1991","journal-title":"J. Auton. Pharm."},{"key":"ref_74","doi-asserted-by":"crossref","first-page":"3D","DOI":"10.1016\/0002-9149(85)91107-5","article-title":"Hypokalemia from beta 2-receptor stimulation by circulating epinephrine","volume":"56","author":"Brown","year":"1985","journal-title":"Am. J. Cardiol."},{"key":"ref_75","doi-asserted-by":"crossref","first-page":"1048","DOI":"10.3389\/fphar.2018.01048","article-title":"Phosphodiesterase-4 Inhibitors for the Treatment of Inflammatory Diseases","volume":"9","author":"Li","year":"2018","journal-title":"Front. Pharm."},{"key":"ref_76","doi-asserted-by":"crossref","first-page":"431","DOI":"10.1016\/j.acvd.2016.02.004","article-title":"Cyclic nucleotide phosphodiesterases in heart and vessels: A therapeutic perspective","volume":"109","author":"Bobin","year":"2016","journal-title":"Arch. Cardiovasc. Dis."},{"key":"ref_77","doi-asserted-by":"crossref","first-page":"983","DOI":"10.2165\/0023210-200822120-00002","article-title":"The role of phosphodiesterases in schizophrenia: Therapeutic implications","volume":"22","author":"Siuciak","year":"2008","journal-title":"CNS Drugs"},{"key":"ref_78","doi-asserted-by":"crossref","first-page":"105","DOI":"10.1016\/j.cellsig.2018.06.005","article-title":"Role of cAMP and phosphodiesterase signaling in liver health and disease","volume":"49","author":"Wahlang","year":"2018","journal-title":"Cell. Signal."},{"key":"ref_79","doi-asserted-by":"crossref","first-page":"114","DOI":"10.3389\/fncom.2013.00114","article-title":"Astrocytic and neuronal accumulation of elevated extracellular K(+) with a 2\/3 K(+)\/Na(+) flux ratio-consequences for energy metabolism, osmolarity and higher brain function","volume":"7","author":"Hertz","year":"2013","journal-title":"Front. Comput. Neurosci."},{"key":"ref_80","doi-asserted-by":"crossref","first-page":"365","DOI":"10.1016\/B978-0-7020-4086-3.00023-0","article-title":"Neurologic complications of electrolyte disturbances and acid-base balance","volume":"119","author":"Espay","year":"2014","journal-title":"Handb. Clin. Neurol."},{"key":"ref_81","doi-asserted-by":"crossref","first-page":"10594","DOI":"10.1021\/acs.jmedchem.9b02170","article-title":"Advances in the Development of Phosphodiesterase-4 Inhibitors","volume":"63","author":"Peng","year":"2020","journal-title":"J. Med. Chem."}],"container-title":["Biology"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/www.mdpi.com\/2079-7737\/11\/11\/1582\/pdf","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2025,10,11]],"date-time":"2025-10-11T01:04:12Z","timestamp":1760144652000},"score":1,"resource":{"primary":{"URL":"https:\/\/www.mdpi.com\/2079-7737\/11\/11\/1582"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2022,10,27]]},"references-count":81,"journal-issue":{"issue":"11","published-online":{"date-parts":[[2022,11]]}},"alternative-id":["biology11111582"],"URL":"https:\/\/doi.org\/10.3390\/biology11111582","relation":{},"ISSN":["2079-7737"],"issn-type":[{"type":"electronic","value":"2079-7737"}],"subject":[],"published":{"date-parts":[[2022,10,27]]}}}