SERCA, or
sarco/
endoplasmic reticulum
The endoplasmic reticulum (ER) is, in essence, the transportation system of the eukaryotic cell, and has many other important functions such as protein folding. It is a type of organelle made up of two subunits – rough endoplasmic reticulum ( ...
Ca2+-
ATPase
ATPases (, Adenosine 5'-TriPhosphatase, adenylpyrophosphatase, ATP monophosphatase, triphosphatase, SV40 T-antigen, ATP hydrolase, complex V (mitochondrial electron transport), (Ca2+ + Mg2+)-ATPase, HCO3−-ATPase, adenosine triphosphatase) are ...
, or SR
Ca2+-
ATPase
ATPases (, Adenosine 5'-TriPhosphatase, adenylpyrophosphatase, ATP monophosphatase, triphosphatase, SV40 T-antigen, ATP hydrolase, complex V (mitochondrial electron transport), (Ca2+ + Mg2+)-ATPase, HCO3−-ATPase, adenosine triphosphatase) are ...
, is a
calcium ATPase
Ca2+ ATPase is a form of P-ATPase that transfers calcium after a muscle has contracted. The two kinds of calcium ATPase are:
*Plasma membrane Ca2+ ATPase (PMCA)
*Sarcoplasmic reticulum Ca2+ ATPase (SERCA)
Plasma membrane Ca2+ ATPase (PMCA)
P ...
-type
P-ATPase
The P-type ATPases, also known as E1-E2 ATPases, are a large group of evolutionarily related ion and lipid pumps that are found in bacteria, archaea, and eukaryotes. P-type ATPases are α-helical bundle primary transporters named based upon th ...
. Its major function is to transport calcium from the cytosol into the sarcoplasmic reticulum.
Function
SERCA is a
P-type ATPase
The P-type ATPases, also known as E1-E2 ATPases, are a large group of evolutionarily related ion and lipid pumps that are found in bacteria, archaea, and eukaryotes. P-type ATPases are α-helical bundle primary transporters named based upon thei ...
.
It resides in the
sarcoplasmic reticulum
The sarcoplasmic reticulum (SR) is a membrane-bound structure found within muscle cells that is similar to the smooth endoplasmic reticulum in other cells. The main function of the SR is to store calcium ions (Ca2+). Calcium ion levels are ke ...
(SR) within
myocyte
A muscle cell is also known as a myocyte when referring to either a cardiac muscle cell (cardiomyocyte), or a smooth muscle cell as these are both small cells. A skeletal muscle cell is long and threadlike with many nuclei and is called a muscl ...
s.
It is a Ca
2+ ATPase that transfers Ca
2+ from the
cytosol
The cytosol, also known as cytoplasmic matrix or groundplasm, is one of the liquids found inside cells (intracellular fluid (ICF)). It is separated into compartments by membranes. For example, the mitochondrial matrix separates the mitochondri ...
of the cell to the
lumen of the SR.
This uses energy from
ATP hydrolysis
ATP hydrolysis is the catabolic reaction process by which chemical energy that has been stored in the high-energy phosphoanhydride bonds in adenosine triphosphate (ATP) is released after splitting these bonds, for example in muscles, by prod ...
during muscle relaxation.
There are 3 major
domains on the cytoplasmic face of SERCA: the
phosphorylation
In chemistry, phosphorylation is the attachment of a phosphate group to a molecule or an ion. This process and its inverse, dephosphorylation, are common in biology and could be driven by natural selection. Text was copied from this source, wh ...
and nucleotide-binding domains, which form the
catalytic site
In biology and biochemistry, the active site is the region of an enzyme where substrate molecules bind and undergo a chemical reaction. The active site consists of amino acid residues that form temporary bonds with the substrate (binding site) a ...
, and the actuator domain, which is involved in the transmission of major
conformational change
In biochemistry, a conformational change is a change in the shape of a macromolecule, often induced by environmental factors.
A macromolecule is usually flexible and dynamic. Its shape can change in response to changes in its environment or oth ...
s.
In addition to its calcium-transporting functions,
SERCA1 generates heat in
brown adipose tissue
Brown adipose tissue (BAT) or brown fat makes up the adipose organ together with white adipose tissue (or white fat). Brown adipose tissue is found in almost all mammals.
Classification of brown fat refers to two distinct cell populations with si ...
and in
skeletal muscle
Skeletal muscles (commonly referred to as muscles) are organs of the vertebrate muscular system and typically are attached by tendons to bones of a skeleton. The muscle cells of skeletal muscles are much longer than in the other types of muscl ...
s. Along with the heat it naturally produces due to its inefficiency in pumping ions, when it binds to a regulator called
sarcolipin
Sarcolipin is a micropeptide protein that in humans is encoded by the ''SLN'' gene.
Function
Sarcoplasmic reticulum Ca2+-ATPases are transmembrane proteins that catalyze the ATP-dependent transport of Ca2+ from the cytosol into the lumen of t ...
it stops pumping and functions solely as an ATP hydrolase. This mechanism of thermogenesis is widespread in mammals and in
endotherm
An endotherm (from Greek ἔνδον ''endon'' "within" and θέρμη ''thermē'' "heat") is an organism that maintains its body at a metabolically favorable temperature, largely by the use of heat released by its internal bodily functions inst ...
ic fishes.
Regulation
The rate at which SERCA moves Ca
2+ across the SR membrane can be controlled by the regulatory protein
phospholamban
Phospholamban, also known as PLN or PLB, is a micropeptide protein that in humans is encoded by the ''PLN'' gene. Phospholamban is a 52-amino acid integral membrane protein that regulates the calcium (Ca2+) pump in cardiac muscle cells.
Funct ...
(PLB/PLN). SERCA is not as active when PLB is bound to it. Increased
β-adrenergic
The adrenergic receptors or adrenoceptors are a class of G protein-coupled receptors that are targets of many catecholamines like norepinephrine (noradrenaline) and epinephrine (adrenaline) produced by the body, but also many medications like beta ...
stimulation reduces the association between SERCA and PLB by the phosphorylation of PLB by
PKA. When PLB is associated with SERCA, the rate of Ca
2+ movement is reduced; upon dissociation of PLB, Ca
2+ movement increases.
Another protein,
calsequestrin
Calsequestrin is a calcium-binding protein that acts as a calcium buffer within the sarcoplasmic reticulum. The protein helps hold calcium in the cisterna of the sarcoplasmic reticulum after a muscle contraction, even though the concentration ...
, 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
concentration gradient
Molecular diffusion, often simply called diffusion, is the thermal motion of all (liquid or gas) particles at temperatures above absolute zero. The rate of this movement is a function of temperature, viscosity of the fluid and the size (mass) o ...
. The SR has a much higher concentration of Ca
2+ (10,000x) inside when compared to the cytoplasmic Ca
2+ 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
Thapsigargin is a non-competitive inhibitor of the sarco/endoplasmic reticulum Ca2+ ATPase (SERCA). Structurally, thapsigargin is classified as a guaianolide, and is extracted from a plant, ''Thapsia garganica''. It is a tumor promoter in ma ...
and induced by
istaroxime
Istaroxime is an investigational drug under development for treatment of acute decompensated heart failure
Originally patented and developed by Sigma-Tau, it was sold to CVie Therapeutics in July 2012.
Heart failure
Istaroxime is a treat ...
.
SERCA function is upregulated in the skeletal muscle of rabbits and in rodent myocardium by thyroid hormones. This mechanism may contribute to the proarrhythmogenic effect of thyrotoxicosis.
Paralogs
There are 3 major
paralogs
Sequence homology is the biological homology between DNA, RNA, or protein sequences, defined in terms of shared ancestry in the evolutionary history of life. Two segments of DNA can have shared ancestry because of three phenomena: either a sp ...
, SERCA1-3, which are expressed at various levels in different cell types.
*
ATP2A1
Sarcoplasmic/endoplasmic reticulum calcium ATPase 1 (SERCA1) is an enzyme that in humans is encoded by the ''ATP2A1'' gene
In biology, the word gene (from , ; "... Wilhelm Johannsen coined the word gene to describe the Mendelian units of h ...
– SERCA1
*
ATP2A2
ATP2A2 also known as sarcoplasmic/endoplasmic reticulum calcium ATPase 2 (SERCA2) is an ATPase associated with Darier's disease and Acrokeratosis verruciformis.
This gene encodes one of the SERCA Ca(2+)-ATPases, which are intracellular pumps lo ...
– SERCA2
*
ATP2A3
Sarcoplasmic/endoplasmic reticulum calcium ATPase 3 is an enzyme that in humans is encoded by the ''ATP2A3'' gene.
This gene encodes one of the SERCA Ca2+-ATPases, which are intracellular pumps located in the sarcoplasmic or endoplasmic reticul ...
– SERCA3
There are additional post-translational isoforms of both SERCA2 and SERCA3, which serve to introduce the possibility of cell-type-specific Ca
2+-reuptake responses as well as increasing the overall complexity of the Ca
2+ signaling mechanism.
References
External links
*
{{ATPases
Transmembrane proteins