Sarco/endoplasmic reticulum Ca2+-ATPase 2a, or SERCA2a, is a protein pump that functions within muscle cells. It is an enzyme, a type of protein that helps speed up chemical reactions in the body. Specifically, SERCA2a is an ATPase, meaning it uses the energy stored in a molecule called adenosine triphosphate (ATP) to power its actions. The primary job of SERCA2a is to move calcium ions from one area of the cell into a storage reservoir. This movement of calcium is fundamental for muscle function.
The Function of SERCA2a in Heart Muscle
The rhythmic beating of the heart is governed by the precise management of calcium ions within its muscle cells, known as cardiomyocytes. Each heartbeat is initiated by a rush of calcium into the main compartment of the cell, the cytoplasm. This influx of calcium allows the heart’s contractile proteins to interact, causing the muscle to shorten and pump blood.
Within these cardiomyocytes is a specialized storage container for calcium called the sarcoplasmic reticulum (SR). After a contraction occurs, the heart muscle must relax to allow its chambers to refill with blood. This relaxation phase, known as diastole, depends on the rapid removal of calcium from the cytoplasm by the SERCA2a pump.
SERCA2a actively pumps calcium ions against their concentration gradient, moving them out of the cytoplasm and back into the sarcoplasmic reticulum. This process restores the low-calcium state in the cytoplasm that is necessary for muscle relaxation. The efficiency of this action directly influences how quickly the heart can relax between beats, with SERCA2a handling about 70% of this calcium removal.
The activity of the SERCA2a pump is not constant; it is tuned by other proteins. A regulator is a small protein called phospholamban (PLN). In its standard, dephosphorylated state, phospholamban acts as a brake, binding to SERCA2a and reducing its pumping efficiency. When the body needs the heart to beat faster or more forcefully, such as during exercise, signaling pathways cause phospholamban to become phosphorylated. This change makes PLN release its hold on SERCA2a, allowing the pump to work at a higher capacity.
The Link Between SERCA2a and Heart Failure
A common feature in many forms of heart failure is a disruption in the normal handling of calcium within cardiomyocytes. Studies on failing human heart tissue consistently show that the expression and activity of the SERCA2a pump are reduced. This decline means fewer functional pumps are available to clear calcium from the cytoplasm after each heartbeat.
When SERCA2a function is impaired, calcium is removed from the cytoplasm more slowly. This inefficiency means the heart muscle does not relax completely or quickly enough between beats. The result is a condition known as diastolic dysfunction, where the heart becomes stiff and has trouble filling with blood.
The problems extend to the contraction phase as well. Because the impaired SERCA2a pumps move less calcium back into the sarcoplasmic reticulum, the SR’s calcium stores become depleted over time. Consequently, for the subsequent heartbeat, there is less calcium available to be released to initiate a contraction. This leads to a weaker force of contraction, a condition called systolic dysfunction.
This combination of poor relaxation (diastolic dysfunction) and weak contraction (systolic dysfunction) is a hallmark of heart failure. The reduced ratio of SERCA2a pumps to their inhibitor, phospholamban, further compounds the issue in the failing heart.
Therapeutic Approaches to Restore SERCA2a
Given the connection between reduced SERCA2a function and heart failure, researchers have explored strategies to restore its activity as a potential treatment. One direct approach is gene therapy. The goal is to increase the number of SERCA2a pumps in the heart cells by introducing a new copy of the gene that codes for it, ATP2A2.
This form of therapy uses a modified, harmless virus, such as an adeno-associated virus (AAV), to act as a delivery vehicle. The AAV is engineered to carry the ATP2A2 gene and, when administered, can transfer it into the cardiomyocytes. The cells then use this new genetic blueprint to synthesize more SERCA2a protein, boosting the heart’s calcium-pumping capacity.
While gene therapy has been a focus, other therapeutic avenues are also being explored. One area of research involves developing small molecule drugs that can directly enhance the function of the existing SERCA2a pumps. These molecules could work by increasing the pump’s affinity for calcium or improving its energy efficiency.
Another strategy focuses on the regulatory proteins that interact with SERCA2a. For instance, developing drugs that block the inhibitory effect of phospholamban could “release the brakes” on the pump. By preventing phospholamban from suppressing SERCA2a activity, these molecules could restore a significant amount of the heart’s calcium-handling capacity.
The Role of SERCA2a in Other Body Tissues
While a focus in cardiology, SERCA2a is not exclusive to the heart. The protein is also expressed in other types of muscle cells throughout the body. It is found in slow-twitch skeletal muscles, which are the muscles used for endurance activities like maintaining posture or long-distance running. In these cells, it serves the same function of managing calcium to control muscle relaxation.
SERCA2a is also present in smooth muscle cells, such as those that line the walls of blood vessels. Here, its role in regulating calcium levels contributes to controlling the tone and contraction of the vessels, which is a factor in blood pressure regulation.
The gene responsible for producing the SERCA2a protein, ATP2A2, can also be linked to diseases outside of the cardiovascular system. Mutations in this single gene can lead to a rare genetic skin disorder known as Darier disease. This condition is characterized by wart-like blemishes on the skin and demonstrates how a defect in a calcium pump can have very different effects depending on the tissue.