• Notch signaling pathway • regulation of ryanodine-sensitive calcium-release channel activity • negative regulation of calcium ion binding • regulation of cardiac conduction • regulation of calcium ion transport • GO:0048553 negative regulation of catalytic activity • regulation of heart contraction • regulation of cytosolic calcium ion concentration • cardiac muscle tissue development • negative regulation of heart contraction • response to testosterone • regulation of the force of heart contraction • regulation of cardiac muscle contraction by regulation of the release of sequestered calcium ion • negative regulation of ATPase activity • regulation of ATPase-coupled calcium transmembrane transporter activity • regulation of calcium ion import • response to zinc ion • cellular calcium ion homeostasis • regulation of relaxation of cardiac muscle • negative regulation of calcium ion transmembrane transporter activity • blood circulation • negative regulation of heart rate • negative regulation of calcium ion import • response to insulin • regulation of cardiac muscle cell contraction • negative regulation of ATPase-coupled calcium transmembrane transporter activity • negative regulation of calcium ion transport • adenylate cyclase-activating adrenergic receptor signaling pathway involved in heart process • regulation of cardiac muscle cell membrane potential • regulation of the force of heart contraction by cardiac conduction • regulation of relaxation of muscle • negative regulation of calcium ion import into sarcoplasmic reticulum • protein homooligomerization • regulation of release of sequestered calcium ion into cytosol by sarcoplasmic reticulum • relaxation of cardiac muscle • calcium ion transport
Sources:Amigo / QuickGO
Orthologs
Species
Human
Mouse
Entrez
5350
n/a
Ensembl
ENSG00000198523
n/a
UniProt
P26678
n/a
RefSeq (mRNA)
NM_002667
n/a
RefSeq (protein)
NP_002658
n/a
Location (UCSC)
Chr 6: 118.55 – 118.56 Mb
n/a
PubMed search
[2]
n/a
Wikidata
View/Edit Human
Function
This protein is found as a pentamer and is a major substrate for the cAMP-dependent protein kinase (PKA) in cardiac muscle. In the unphosphorylated state, phospholamban is an inhibitor of cardiac muscle sarcoplasmic reticulum Ca2+-ATPase (SERCA2)[5] which transports calcium from cytosol into the sarcoplasmic reticulum. When phosphorylated (by PKA) - disinhibition of Ca2+-ATPase of SR leads to faster Ca2+ uptake into the sarcoplasmic reticulum, thereby contributing to the lusitropic response elicited in heart by beta-agonists.[6] The protein is a key regulator of cardiac diastolic function. Mutations in this gene are a cause of inherited human dilated cardiomyopathy with refractory congestive heart failure.[7]
When phospholamban is phosphorylated by PKA, its ability to inhibit SERCA2 is lost.[8] Thus, activators of PKA, such as the beta-adrenergic agonist epinephrine (released by sympathetic stimulation), may enhance the rate of cardiac myocyte relaxation. In addition, since SERCA2 is more active, the next action potential will cause an increased release of calcium, resulting in increased contraction (positive inotropic effect). When phospholamban is not phosphorylated, such as when PKA is inactive, it can interact with and inhibit SERCA. The overall effect of phospholamban is to decrease contractility and the rate of muscle relaxation, thereby decreasing stroke volume and heart rate, respectively.[9]
Clinical significance
Gene knockout of phospholamban results in animals with hyperdynamic hearts, with little apparent negative consequence.[10]
Mutations in this gene are a cause of inherited human dilated cardiomyopathy with refractory congestive heart failure.[11][12]
Discovery
Phospholamban was discovered by Arnold Martin Katz and coworkers in 1974.[13]
Interactions
PLN has been shown to interact with SLN[14][15] and SERCA1.[15][16][17]
References
^ a b cGRCh38: Ensembl release 89: ENSG00000198523 - Ensembl, May 2017
^"Human PubMed Reference:". National Center for Biotechnology Information, U.S. National Library of Medicine.
^Fujii J, Zarain-Herzberg A, Willard HF, Tada M, MacLennan DH (June 1991). "Structure of the rabbit phospholamban gene, cloning of the human cDNA, and assignment of the gene to human chromosome 6". The Journal of Biological Chemistry. 266 (18): 11669–75. doi:10.1016/S0021-9258(18)99009-5. PMID 1828805.
^Rodriguez P, Kranias EG (December 2005). "Phospholamban: a key determinant of cardiac function and dysfunction". Archives des Maladies du Coeur et des Vaisseaux. 98 (12): 1239–43. PMID 16435604.
^Hagemann D, Xiao RP (February 2002). "Dual site phospholamban phosphorylation and its physiological relevance in the heart". Trends in Cardiovascular Medicine. 12 (2): 51–6. doi:10.1016/S1050-1738(01)00145-1. PMID 11852250.
^"Entrez Gene: PLN phospholamban".
^Medical Physiology. Philadelphia: Saunders. 2004. ISBN 0-8089-2333-1.
^Brittsan AG, Kranias EG (December 2000). "Phospholamban and cardiac contractile function". Journal of Molecular and Cellular Cardiology. 32 (12): 2131–9. doi:10.1006/jmcc.2000.1270. PMID 11112989.
^Luo W, Grupp IL, Harrer J, Ponniah S, Grupp G, Duffy JJ, Doetschman T, Kranias EG (September 1994). "Targeted ablation of the phospholamban gene is associated with markedly enhanced myocardial contractility and loss of beta-agonist stimulation". Circulation Research. 75 (3): 401–9. doi:10.1161/01.res.75.3.401. PMID 8062415.
^Schmitt JP, Kamisago M, Asahi M, Li GH, Ahmad F, Mende U, Kranias EG, MacLennan DH, Seidman JG, Seidman CE (February 2003). "Dilated cardiomyopathy and heart failure caused by a mutation in phospholamban". Science. 299 (5611): 1410–3. doi:10.1126/science.1081578. PMID 12610310. S2CID 12253445.
^Eijgenraam TR, Boukens BJ, Boogerd CJ, Schouten EM, van de Kolk CW, Stege NM, te Rijdt WP, Hoorntje ET, van der Zwaag PA, van Rooij E, van Tintelen JP, van den Berg MP, van der Meer P, van der Velden J, Silljé HH, de Boer RA (17 June 2020). "The phospholamban p.(Arg14del) pathogenic variant leads to cardiomyopathy with heart failure and is unreponsive to standard heart failure therapy". Scientific Reports. 10 (1): 9819. Bibcode:2020NatSR..10.9819E. doi:10.1038/s41598-020-66656-9. PMC 7300032. PMID 32555305.
^Tada M, Kirchberger MA, Repke DI, Katz AM (October 1974). "The stimulation of calcium transport in cardiac sarcoplasmic reticulum by adenosine 3':5'-monophosphate-dependent protein kinase". The Journal of Biological Chemistry. 249 (19): 6174–80. doi:10.1016/S0021-9258(19)42237-0. PMID 4371608.
^Asahi M, Sugita Y, Kurzydlowski K, De Leon S, Tada M, Toyoshima C, MacLennan DH (April 2003). "Sarcolipin regulates sarco(endo)plasmic reticulum Ca2+-ATPase (SERCA) by binding to transmembrane helices alone or in association with phospholamban". Proceedings of the National Academy of Sciences of the United States of America. 100 (9): 5040–5. Bibcode:2003PNAS..100.5040A. doi:10.1073/pnas.0330962100. PMC 154294. PMID 12692302.
^ a bAsahi M, Kurzydlowski K, Tada M, MacLennan DH (July 2002). "Sarcolipin inhibits polymerization of phospholamban to induce superinhibition of sarco(endo)plasmic reticulum Ca2+-ATPases (SERCAs)". The Journal of Biological Chemistry. 277 (30): 26725–8. doi:10.1074/jbc.C200269200. PMID 12032137.
^Asahi M, Kimura Y, Kurzydlowski K, Tada M, MacLennan DH (November 1999). "Transmembrane helix M6 in sarco(endo)plasmic reticulum Ca(2+)-ATPase forms a functional interaction site with phospholamban. Evidence for physical interactions at other sites". The Journal of Biological Chemistry. 274 (46): 32855–62. doi:10.1074/jbc.274.46.32855. PMID 10551848.
^Asahi M, Green NM, Kurzydlowski K, Tada M, MacLennan DH (August 2001). "Phospholamban domain IB forms an interaction site with the loop between transmembrane helices M6 and M7 of sarco(endo)plasmic reticulum Ca2+ ATPases". Proceedings of the National Academy of Sciences of the United States of America. 98 (18): 10061–6. Bibcode:2001PNAS...9810061A. doi:10.1073/pnas.181348298. PMC 56915. PMID 11526231.
This article incorporates text from the United States National Library of Medicine, which is in the public domain.
External links
PDBe-KB provides an overview of all the structure information available in the PDB for Human Cardiac phospholamban