Ca2+ transport into the sarcoplasmic reticulum (SR) occurs via the action of the SR Ca2+ pump. As in skeletal muscle, 1 molecule of ATP has to be hydrolyzed per 2 molecules of Ca2+ that are pumped against a large concentration gradient into the lumen of the SR. The SR Ca2+-ATPase, called sarco(endo)plasmic reticulum Ca-ATPase (SERCA), is regulated by phospholamban (described below). Ca2+ is released from SR through a Ca2+-sensitive SR Ca2+ release channel. The channel tightly binds ryanodine and, therefore, it is also referred to as the ryanodine receptor (RYR).
Separation of rat heart myofibril proteins by gel electrophoresis (From Kopp and Barany, 1979). Gel 1, myofibrils; gel 2, beef heart myosin; gel 3, beef heart troponin; and gel 4, beef heart TM. For other details see the text.
Ca2+ induced Ca2+ release (CICR) CICR is specific for the heart. The small amount of Ca2+ that enters the cell through voltage dependent plasmalemmal Ca2+ channels (which open in response to the action potential) causes a much larger amount of Ca2+ to be released from within the SR.
Calsequestrin is a Ca2+ binding protein that is located within the lumen of SR and is primarily responsible for Ca2+ storage within the SR.
Phospholamban (PLB): It is a pentamer made up of five identical subunits, each 6,000 dalton (52 amino acid residues). PLB is found in cardiac, slow skeletal and smooth muscle but it is absent in fast skeletal muscle. The protein is associated with the Ca2+-pump ATPase in the membrane of the sarcoplasmic reticulum. The flexible N-terminus on which the phosphorylation sites are located extends out into the cytoplasm of the cardiac muscle cell. The phosphorylation site at serine 16 is a substrate for PKA, whereas threonine 17 is phosphorylated by a Ca2+-calmodulin dependent protein kinase. Phosphorylation of PLB by PKA increases the rate of Ca2+ transport and the Ca2+-sensitivity of the Ca2+-pump and thereby facilitates relaxation in heart exposed to p-adrenergic agonists (Katz, 1992; Perry, 1996). Phosphorylation of PLB by a Ca2+-calmodulin dependent protein kinase also stimulates Ca2+-uptake in vitro, but its physiological significance is not known.
Research on the physiological significance of PLB reached an unexpected turn when a PLB deficient mice was generated, the "PLB knockout (KO) mouse". Surprisingly, there were no detrimental effects in the performance of such animals or in the function of their isolated heart. For instance, the basal contractility and the Ca2+-transient of myocytes isolated from PLB deficient hearts were enhanced compared with cells isolated from wild type animals. Furthermore, the contractility of PLB-deficient myocytes could be further enhanced by the p-adrenergic agonist, isoproterenol. These results demonstrate that in the absence of PLB, there are mechanisms available in the heart to adjust its activity, and that phosphorylation of sites other than PLB may play an important role in regulation of contraction-relaxation dynamics of heart responding to p-adrenergic stimulation (Wolska et al.,1996)
Factors controlling the Ca2+ release from SR:
Ryanodine (a plant derived alkaloid) is a very effective drug that alters the SR Ca2+ release channel.
Phospholamban phosphorylation by PKA.
Thapsigargin and cyclopiazonic acid (CPA) that block the Ca2+ pump.
Digitalis, a drug that inhibits the Na+/K+ pump leading to a small increase in intracellular Na+. This decreases the rate at which the Na+/Ca2+ exchanger extrudes Ca2+ from the cell and thus leads to enhanced loading of the SR.
Was this article helpful?