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Phospholamban, also known as PLN, is a protein that in humans is encoded by the PLN gene.^[1] Phospholamban is a 52-amino acid integral membrane protein that regulates the Ca²⁺ pump in cardiac muscle and skeletal muscle cells.^[2]

Function

The protein encoded by this gene is found as a pentamer and is a major substrate for the cAMP-dependent protein kinase ( PKA ) in cardiac muscle. The protein is an inhibitor of cardiac muscle sarcoplasmic reticulum Ca⁺⁺-ATPase ( SERCA ) in the unphosphorylated state, but inhibition is relieved upon phosphorylation of the protein. The subsequent activation of the Ca⁺⁺ pump leads to shorter intervals between contractions, thereby contributing to the lusitropic response elicited in heart by beta-agonists. 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.^[3]

When phospholamban is phosphorylated by PKA its ability to inhibit the sarcoplasmic reticulum calcium pump (SERCA) is lost.^[4] 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 SERCA 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 the rate of muscle relaxation and contractility , thereby decreasing heart rate and stroke volume, respectively.^[5]

Clinical significance

Gene knockout of phospholamban results in animals with hyperdynamic hearts, with little apparent negative consequence.^[6]

Mutations in this gene are a cause of inherited human dilated cardiomyopathy with refractory congestive heart failure .^[7]

Discovery

Phospholamban was discovered by Arnold Katz and coworkers in 1974.^[8]

Interactions

PLN (gene) has been shown to interact with SLN^[9]^[10] and ATP2A1.^[10]^[11]^[12]

References

^ 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". J. Biol. Chem. 266 (18): 11669–75. PMID 1828805. http://www.jbc.org/cgi/pmidlookup?view=long&pmid=1828805.
^ Rodriguez P, Kranias EG (December 2005). "Phospholamban: a key determinant of cardiac function and dysfunction". Arch Mal Coeur Vaiss 98 (12): 1239–43. PMID 16435604.
^ "Entrez Gene: PLN phospholamban". http://www.ncbi.nlm.nih.gov/sites/entrez?Db=gene&Cmd=ShowDetailView&TermToSearch=5350.
^ Medical Physiology. Philadelphia: Saunders. 2004. ISBN 0-8089-2333-1.
^ Brittsan AG, Kranias EG (December 2000). "Phospholamban and cardiac contractile function". J. Mol. Cell. Cardiol. 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". Circ. Res. 75 (3): 401–9. 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.
^ 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". J Biol Chem 10 (249(19)): 6174–80. PMID 4371608.
^ Asahi, Michio; Sugita Yuji, Kurzydlowski Kazimierz, De Leon Stella, Tada Michihiko, Toyoshima Chikashi, MacLennan David H (Apr. 2003). "Sarcolipin regulates sarco(endo)plasmic reticulum Ca2+-ATPase (SERCA) by binding to transmembrane helices alone or in association with phospholamban". Proc. Natl. Acad. Sci. U.S.A. (United States) 100 (9): 5040–5. DOI:10.1073/pnas.0330962100. ISSN 0027-8424. PMC 154294. PMID 12692302. //www.pubmedcentral.nih.gov/articlerender.fcgi?tool=pmcentrez&artid=154294.
^ ^a ^b Asahi, Michio; Kurzydlowski Kazimierz, Tada Michihiko, MacLennan David H (Jul. 2002). "Sarcolipin inhibits polymerization of phospholamban to induce superinhibition of sarco(endo)plasmic reticulum Ca2+-ATPases (SERCAs)". J. Biol. Chem. (United States) 277 (30): 26725–8. DOI:10.1074/jbc.C200269200. ISSN 0021-9258. PMID 12032137.
^ Asahi, M; Kimura Y, Kurzydlowski K, Tada M, MacLennan D H (Nov. 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". J. Biol. Chem. (UNITED STATES) 274 (46): 32855–62. DOI:10.1074/jbc.274.46.32855. ISSN 0021-9258. PMID 10551848.
^ Asahi, M; Green N M, Kurzydlowski K, Tada M, MacLennan D H (Aug. 2001). "Phospholamban domain IB forms an interaction site with the loop between transmembrane helices M6 and M7 of sarco(endo)plasmic reticulum Ca2+ ATPases". Proc. Natl. Acad. Sci. U.S.A. (United States) 98 (18): 10061–6. DOI:10.1073/pnas.181348298. ISSN 0027-8424. PMC 56915. PMID 11526231. //www.pubmedcentral.nih.gov/articlerender.fcgi?tool=pmcentrez&artid=56915.

External links

UMich Orientation of Proteins in Membranes families/superfamily-70 - Orientations of phospholamban and sarcolipin in membrane]

This article incorporates text from the United States National Library of Medicine, which is in the public domain.

UpToDate Contents

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1. 拡張型心筋症の遺伝学 genetics of dilated cardiomyopathy
2. 心筋における興奮収縮連関 excitation contraction coupling in myocardium
3. 甲状腺機能亢進症の心血管系への影響 cardiovascular effects of hyperthyroidism
4. 甲状腺機能低下症の心血管系への影響 cardiovascular effects of hypothyroidism
5. 拡張能障害の細胞学的機序 cellular mechanisms of diastolic dysfunction

English Journal

Involvement of L-type calcium channel and serca2a in myocardial dysfunction induced by obesity.

Leopoldo AS, Lima-Leopoldo AP, Sugizaki MM, Nascimento AF, de Campos DH, Luvizotto Rde A, Castardeli E, Alves CA, Brum PC, Cicogna AC.SourceDepartment of Clinical and Cardiology, School of Medicine, UNESP- State University Julio Mesquita Filho, Botucatu, Sao Paulo, Brazil; Department of Sports, Center of Physical Education and Sports, UFES - Federal University of Espirito Santo, Vitoria, Espirito Santo, Brazil. andresoaresleopoldo@gmail.com.
Journal of cellular physiology.J Cell Physiol.2011 Nov;226(11):2934-42. doi: 10.1002/jcp.22643.
Obesity has been shown to impair myocardial performance. Nevertheless, the mechanisms underlying the participation of calcium (Ca(2+) ) handling on cardiac dysfunction in obesity models remain unknown. L-type Ca(2+) channels and sarcoplasmic reticulum (SR) Ca(2+) -ATPase (SERCA2a), may contribute to
PMID 21302294

A full range of mouse sinoatrial node AP firing rates requires protein kinase A-dependent calcium signaling.

Liu J, Sirenko S, Juhaszova M, Ziman B, Shetty V, Rain S, Shukla S, Spurgeon HA, Vinogradova TM, Maltsev VA, Lakatta EG.SourceLaboratory of Cardiovascular Science, Intramural Research Program, Gerontology Research Center, National Institute on Aging, National Institutes of Health, 5600 Nathan Shock Drive, Baltimore MD 21224, USA; Muscle Cell Function Laboratory, School Of Medical Sciences, Anderson Stuart Building (F13), University Of Sydney, Sydney Nsw 2006 Australia.
Journal of molecular and cellular cardiology.J Mol Cell Cardiol.2011 Nov;51(5):730-9. Epub 2011 Aug 4.
Recent perspectives on sinoatrial nodal cell (SANC)(?) function indicate that spontaneous sarcoplasmic reticulum (SR) Ca(2+) cycling, i.e. an intracellular "Ca(2+) clock," driven by cAMP-mediated, PKA-dependent phosphorylation, interacts with an ensemble of surface membrane electrogenic molecules
PMID 21840316

Japanese Journal

Overexpression of PEP-19 Suppresses Angiotensin II–Induced Cardiomyocyte Hypertrophy

, , , , , , ,
Journal of Pharmacological Sciences 125(3), 274-282, 2014
… Moreover, PEP-19 partially ameliorates angiotensin II–induced elevation of phospho-phospholamban (Thr-17) and sarcoplasmic reticulum Ca2+ release in cardiomyocytes. …
NAID 130004438637

Antenatal Glucocorticoid Administration Enhances Sarcoplasmic Reticulum Calcium Transport ATPase 2a and Phospholamban Expression in The Immature Fetal Rat Heart

Sakurai Kenzo,Takeba Yuko,Mizuno Masanori [他]
Journal of St. Marianna University 4(2), 69-80, 2013-12
NAID 40019942534

Comparative analysis of cardiomyocyte differentiation from human embryonic stem cells under 3-D and 2-D culture conditions(CELL AND TISSUE ENGINEERING)

Pal Rajarshi,Mamidi Murali Krishna,Das Anjan Kumar [他],Bhonde Ramesh
Journal of bioscience and bioengineering 115(2), 200-206, 2013-02
… levels of functional heart-specific markers such as MLC-2A/2V, cTnT, ANP, Phospholamban, α-MHC and KV4.3 were substantially up-regulated in 3-D compared to 2-D cultures. …
NAID 110009592572

Related Pictures

Frontiers | The role of CaMKII regulation of phospholamban activity in heart disease Human Phospholamban Pentamer Photograph by Laguna Design/science Photo Library Adrenergic Agents - Pharmacology - An Illustrated Review Phospholamban Membrane Protein Molecule Photograph by Laguna Design Phospholamban: a crucial regulator of cardiac contractility | Nature Reviews Molecular CaMKII regulation of phospholamban and SR Ca2+ load - Heart Rhythm

★リンクテーブル★

リンク元

「ホスホランバン」

Phospholamban
	; PDB rendering based on 1fjk.
Available structures
PDB	Ortholog search: PDBe, RCSB
List of PDB id codes
	1PLP, 1ZLL, 2HYN
Identifiers
Symbols	PLN; CMD1P; CMH18; PLB
External IDs	OMIM: 172405 MGI: 97622 HomoloGene: 2002 GeneCards: PLN Gene
Gene Ontology
Molecular function	• calcium channel regulator activity; • protein binding; • ATPase inhibitor activity;
Cellular component	• mitochondrion; • membrane; • integral to membrane; • sarcoplasmic reticulum; • mitochondrial membrane; • vesicle; • protein complex;
Biological process	• regulation of the force of heart contraction; • cellular calcium ion homeostasis; • blood circulation; • negative regulation of heart contraction; • cardiac muscle tissue development; • regulation of calcium ion transport;
	Sources: Amigo / QuickGO
RNA expression pattern
	More reference expression data
Orthologs
	This box: view; talk; edit;

	Phospholamban pentamer
Identifiers
Symbol	Phospholamban
Pfam	PF04272
InterPro	IPR005984
SCOP	1fjk
SUPERFAMILY	1fjk
TCDB	8.A.11
OPM superfamily	70
OPM protein	1zll
Available protein structures:
Pfam	structures
PDB	RCSB PDB; PDBe
PDBsum	structure summary

　　[★]

英: phospholamban
関: 小胞体

M.W.：6.0kDa
5量体を形成。心筋の小胞体の膜上に存在。
小胞体のCa²⁺輸送制御タンパク質である。小胞体のCaポンプに結合して小胞体へのCaへの取り込みを阻害している。PKAによりリン酸化を受けるとこの抑制が解除され、小胞体へのCa²⁺取り込みが促進される。これにより心筋の陽性変力作用を呈する (SPC.222)

[pmid1828805-0] 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". J. Biol. Chem. 266 (18): 11669–75. PMID 1828805. http://www.jbc.org/cgi/pmidlookup?view=long&pmid=1828805.

[pmid16435604-1] Rodriguez P, Kranias EG (December 2005). "Phospholamban: a key determinant of cardiac function and dysfunction". Arch Mal Coeur Vaiss 98 (12): 1239–43. PMID 16435604.

[2] "Entrez Gene: PLN phospholamban". http://www.ncbi.nlm.nih.gov/sites/entrez?Db=gene&Cmd=ShowDetailView&TermToSearch=5350.

[isbn0-8089-2333-1-3] Medical Physiology. Philadelphia: Saunders. 2004. ISBN 0-8089-2333-1.

[pmid11112989-4] Brittsan AG, Kranias EG (December 2000). "Phospholamban and cardiac contractile function". J. Mol. Cell. Cardiol. 32 (12): 2131–9. DOI:10.1006/jmcc.2000.1270. PMID 11112989.

[pmid8062415-5] 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". Circ. Res. 75 (3): 401–9. PMID 8062415.

[pmid12610310-6] 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.

[pmid4371608-7] 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". J Biol Chem 10 (249(19)): 6174–80. PMID 4371608.

[pmid12692302-8] Asahi, Michio; Sugita Yuji, Kurzydlowski Kazimierz, De Leon Stella, Tada Michihiko, Toyoshima Chikashi, MacLennan David H (Apr. 2003). "Sarcolipin regulates sarco(endo)plasmic reticulum Ca2+-ATPase (SERCA) by binding to transmembrane helices alone or in association with phospholamban". Proc. Natl. Acad. Sci. U.S.A. (United States) 100 (9): 5040–5. DOI:10.1073/pnas.0330962100. ISSN 0027-8424. PMC 154294. PMID 12692302. //www.pubmedcentral.nih.gov/articlerender.fcgi?tool=pmcentrez&artid=154294.

[pmid12032137-9] Asahi, Michio; Kurzydlowski Kazimierz, Tada Michihiko, MacLennan David H (Jul. 2002). "Sarcolipin inhibits polymerization of phospholamban to induce superinhibition of sarco(endo)plasmic reticulum Ca2+-ATPases (SERCAs)". J. Biol. Chem. (United States) 277 (30): 26725–8. DOI:10.1074/jbc.C200269200. ISSN 0021-9258. PMID 12032137.

[pmid10551848-10] Asahi, M; Kimura Y, Kurzydlowski K, Tada M, MacLennan D H (Nov. 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". J. Biol. Chem. (UNITED STATES) 274 (46): 32855–62. DOI:10.1074/jbc.274.46.32855. ISSN 0021-9258. PMID 10551848.

[pmid11526231-11] Asahi, M; Green N M, Kurzydlowski K, Tada M, MacLennan D H (Aug. 2001). "Phospholamban domain IB forms an interaction site with the loop between transmembrane helices M6 and M7 of sarco(endo)plasmic reticulum Ca2+ ATPases". Proc. Natl. Acad. Sci. U.S.A. (United States) 98 (18): 10061–6. DOI:10.1073/pnas.181348298. ISSN 0027-8424. PMC 56915. PMID 11526231. //www.pubmedcentral.nih.gov/articlerender.fcgi?tool=pmcentrez&artid=56915.

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phospholamban