View source for SERCA

{{Short description|Calcium ATPase-type P-ATPase}}
'''SERCA''', or '''[[sarcoplasmic reticulum|sarcoplasmic]]/[[endoplasmic reticulum]] [[Calcium|Ca]]<sup>2+</sup>-[[ATPase]]''', or '''SR [[Calcium|Ca]]<sup>2+</sup>-[[ATPase]]''', is a [[calcium ATPase]]-type [[P-type ATPase|P-ATPase]]. Its major function is to transport calcium from the cytosol into the sarcoplasmic reticulum.
==Function==
SERCA is a [[P-type ATPase]].<ref name=":0">{{Citation|last=Marín-García|first=José|title=Chapter 23 - Gene- and Cell-Based Therapy for Cardiovascular Disease|date=2014-01-01|url=http://www.sciencedirect.com/science/article/pii/B9780124045996000238|work=Post-Genomic Cardiology (Second Edition)|pages=783–833|editor-last=Marín-García|editor-first=José|place=Boston|publisher=Academic Press|language=en|doi=10.1016/b978-0-12-404599-6.00023-8|isbn=978-0-12-404599-6|access-date=2020-12-28}}</ref> It resides in the [[sarcoplasmic reticulum]] (SR) within [[myocyte]]s.<ref name=":0" /> It is a Ca<sup>2+</sup> ATPase that transfers Ca<sup>2+</sup> from the [[cytosol]] of the cell to the [[lumen (anatomy)|lumen]] of the SR.<ref name=":0" /> This uses energy from [[ATP hydrolysis]] during muscle relaxation.<ref name=":0" />
There are 3 major [[protein domain|domains]] on the cytoplasmic face of SERCA: the [[phosphorylation]] and nucleotide-binding domains, which form the [[active site|catalytic site]], and the actuator domain, which is involved in the transmission of major [[conformational change]]s.
In addition to its calcium-transporting functions, [[ATP2A1|SERCA1]] generates heat in [[brown adipose tissue]] and in [[skeletal muscle]]s.<ref>{{cite journal |author1=de Meis L |author2=Oliveira GM |author3=Arruda AP |author4=Santos R |author5=Costa RM |author6=Benchimol M |title=The thermogenic activity of rat brown adipose tissue and rabbit white muscle Ca<sup>2+</sup>-ATPase |journal=IUBMB Life |volume=57 |issue=4–5 |pages=337–45 |year=2005 |pmid=16036618 |doi=10.1080/15216540500092534 |doi-access=free }}</ref><ref>{{cite journal |author1=Arruda AP |author2=Nigro M |author3=Oliveira GM |author4=de Meis L |title=Thermogenic activity of Ca<sup>2+</sup>-ATPase from skeletal muscle heavy sarcoplasmic reticulum: the role of ryanodine Ca<sup>2+</sup> channel |journal=Biochim. Biophys. Acta |volume=1768 |issue=6 |pages=1498–505 |date=June 2007 |pmid=17466935 |doi=10.1016/j.bbamem.2007.03.016 |doi-access=free }}</ref> Along with the heat it naturally produces due to its inefficiency in pumping {{chem|Ca|2+}} ions, when it binds to a regulator called [[sarcolipin]] it stops pumping and functions solely as an ATP hydrolase. This mechanism of thermogenesis is widespread in mammals and in [[endotherm]]ic fishes.<ref name=Bal2020>{{Cite journal| doi = 10.1098/rstb.2019.0135| volume = 375| issue = 1793| pages = 20190135| last1 = Bal| first1 = Naresh C.| last2 = Periasamy| first2 = Muthu| title = Uncoupling of sarcoendoplasmic reticulum calcium ATPase pump activity by sarcolipin as the basis for muscle non-shivering thermogenesis| journal = Philosophical Transactions of the Royal Society B: Biological Sciences| date = 2020-03-02| pmid = 31928193| url= | pmc = 7017432}}</ref><ref name=Legendre2020>{{Cite journal| doi = 10.1098/rstb.2019.0136| volume = 375| issue = 1793| pages = 20190136| last1 = Legendre| first1 = Lucas J.| last2 = Davesne| first2 = Donald| title = The evolution of mechanisms involved in vertebrate endothermy| journal = Philosophical Transactions of the Royal Society B: Biological Sciences| date = 2020-03-02| pmid = 31928191| pmc = 7017440| doi-access = free}}</ref>
==Regulation==
The rate at which SERCA moves Ca<sup>2+</sup> across the SR membrane can be controlled by the regulatory protein [[phospholamban]] (PLB/PLN). SERCA is not as active when PLB is bound to it. Increased [[β-adrenergic]] stimulation reduces the association between SERCA and PLB by the phosphorylation of PLB by [[Protein kinase A|PKA]].<ref>{{cite journal|last=MacLennan|first=David H.|author2=Kranias, Evangelia G. |title=Phospholamban: a crucial regulator of cardiac contractility|journal=Nature Reviews Molecular Cell Biology|date=July 2003|volume=4|issue=7|pages=566–577|doi=10.1038/nrm1151|pmid=12838339|s2cid=3050392}}</ref>  When PLB is associated with SERCA, the rate of Ca<sup>2+</sup> movement is reduced; upon dissociation of PLB, Ca<sup>2+</sup> movement increases.
Activity regulation of SERCA can also involve phosphorylation of SERCA itself by interaction with [[Glycogen synthase kinase-3 beta|GSK3β]]. Phosphorylation of [[ATP2A2|SERCA2a]] at S663 was shown to reduce SERCA2a activity.<ref>{{Cite journal |last1=Gonnot |first1=Fabrice |last2=Boulogne |first2=Laura |last3=Brun |first3=Camille |last4=Dia |first4=Maya |last5=Gouriou |first5=Yves |last6=Bidaux |first6=Gabriel |last7=Chouabe |first7=Christophe |last8=Crola Da Silva |first8=Claire |last9=Ducreux |first9=Sylvie |last10=Pillot |first10=Bruno |last11=Kaczmarczyk |first11=Andrea |last12=Leon |first12=Christelle |last13=Chanon |first13=Stephanie |last14=Perret |first14=Coralie |last15=Sciandra |first15=Franck |date=2023-06-08 |title=SERCA2 phosphorylation at serine 663 is a key regulator of Ca2+ homeostasis in heart diseases |journal=Nature Communications |language=en |volume=14 |issue=1 |pages=3346 |doi=10.1038/s41467-023-39027-x |issn=2041-1723 |pmc=10250397 |pmid=37291092}}</ref>
Another protein, [[calsequestrin]], binds calcium within the SR and helps to reduce the concentration of free calcium within the SR, which assists SERCA so that it does not have to pump against such a high [[molecular diffusion|concentration gradient]]. The SR has a much higher concentration of Ca<sup>2+</sup> (10,000x) inside when compared to the cytoplasmic Ca<sup>2+</sup> concentration. SERCA2 can be regulated by microRNAs, for instance miR-25 suppresses SERCA2 in heart failure.
For experimental purposes, SERCA can be inhibited by [[thapsigargin]] and induced by [[istaroxime]].
SERCA function is upregulated in the skeletal muscle of rabbits<ref>{{cite journal |last1=Arruda |first1=AP |last2=Oliveira |first2=GM |last3=Carvalho |first3=DP |last4=De Meis |first4=L |title=Thyroid hormones differentially regulate the distribution of rabbit skeletal muscle Ca(2+)-ATPase (SERCA) isoforms in light and heavy sarcoplasmic reticulum. |journal=Molecular Membrane Biology |date=November 2005 |volume=22 |issue=6 |pages=529–37 |doi=10.1080/09687860500412257 |pmid=16373324|s2cid=29949157 |doi-access=free }}</ref> and in rodent myocardium<ref>{{cite journal |last1=Chang |first1=KC |last2=Figueredo |first2=VM |last3=Schreur |first3=JH |last4=Kariya |first4=K |last5=Weiner |first5=MW |last6=Simpson |first6=PC |last7=Camacho |first7=SA |title=Thyroid hormone improves function and Ca2+ handling in pressure overload hypertrophy. Association with increased sarcoplasmic reticulum Ca2+-ATPase and alpha-myosin heavy chain in rat hearts. |journal=The Journal of Clinical Investigation |date=1 October 1997 |volume=100 |issue=7 |pages=1742–9 |doi=10.1172/JCI119699 |pmid=9312172|pmc=508357 }}</ref><ref>{{cite journal |last1=Kaasik |first1=Allen |last2=Minajeva |first2=Ave |last3=Paju |first3=Kalju |last4=Eimre |first4=Margus |last5=Seppet |first5=Enn K. |title=Thyroid hormones differentially affect sarcoplasmic reticulum function in rat atria and ventricles |journal=Molecular and Cellular Biochemistry |date=1997 |volume=176 |issue=1/2 |pages=119–126 |doi=10.1023/A:1006887231150|pmid=9406153 |s2cid=8199751 }}</ref> by thyroid hormones. This mechanism may contribute to the proarrhythmogenic effect of thyrotoxicosis.<ref>{{cite journal |last1=Müller |first1=Patrick |last2=Leow |first2=Melvin Khee-Shing |last3=Dietrich |first3=Johannes W. |title=Minor perturbations of thyroid homeostasis and major cardiovascular endpoints—Physiological mechanisms and clinical evidence |journal=Frontiers in Cardiovascular Medicine |date=15 August 2022 |volume=9 |pages=942971 |doi=10.3389/fcvm.2022.942971|doi-access=free |pmid=36046184|pmc=9420854 }}</ref>
==Paralogs==
There are 3 major [[Homology (biology)#Sequence homology|paralogs]], SERCA1-3, which are expressed at various levels in different cell types.
* [[ATP2A1]] – SERCA1
* [[ATP2A2]] – SERCA2
* [[ATP2A3]] – SERCA3
There are additional post-translational isoforms of both SERCA2 and SERCA3, which serve to introduce the possibility of cell-type-specific Ca<sup>2+</sup>-reuptake responses as well as increasing the overall complexity of the Ca<sup>2+</sup> signaling mechanism.
== References ==
{{Reflist}}
== External links ==
* {{MeshName|Sarcoplasmic+Reticulum+Calcium-Transporting+ATPases}}
{{Ion pumps}}
{{ATPases}}
[[Category:Transmembrane proteins]]