Muscle SERCA

The smooth endoplasmic reticulum calcium pumps (SERCA) found in brain were first identified in sarcoplasmic reticulum. The three isoforms of SERCA are products of separate genes SERCA-1 is expressed in fast-twitch skeletal muscle SERCA-2a in cardiac/slow-twitch muscle SERCA-2b, an alternatively spliced form, is expressed in smooth muscle and non-muscle tissues SERCA-3 is... 

Sarcoplasmic reticulum (SR) is a form of the smoothfaced endoplasmic reticulum (ER) in muscles. It functions as an intracellular Ca2+ store for muscle contraction. Ca2+ is energetically sequestered into the SR by Ca2+-pump/sarcoplasmic endoplasmic reticulum Ca2+-ATPase (SERCA) and released via Ca2+ release channels on stimuli (ryanodine receptor in striated muscles and inositol 1,4,5-trisphosphate receptor in most smooth muscles). Endoplasmic reticulum in non-muscle tissues also functions as an intracellular Ca2+ store. 

In striated muscles, SR is well developed to surround the myofibrils and is divided into two parts, the terminal cisternae (TC) and longitudinal tubules (LT). TC forms triad (skeletal muscle) or dyad (heart) structure with transverse tubules. The ryanodine receptor is located only in the TC, whereas the Ca2+ pump/SERCA is densely packed in both TC and LT. 

Our discussion here will concentrate on the various forms of the Ca " transport ATPases that occur in the sarcoplasmic reticulum of muscle cells of diverse fiber types and in the endoplasmic reticulum of nonmuscle cells (SERCA). The structure of these enzymes will be compared with the Ca transport ATPases of surface membranes (PMCA) [3,29-32,34] and with other ATP-dependent ion pumps that transport Na, K, andH [46,50-52]. 

SERCA la denotes the Ca -ATPase of adult fast-twitch skeletal muscle with glycine at its C-terminus in the rabbit [53,58], and alanine at the C-terminus in the chicken [59,60]. The C-terminus of the lobster enzyme is apparently blocked [59]. 

SERCA-type -ATPases from non-mammalian cells (SERCAMED) Sequences of SERCA-type Ca -ATPases were also obtained from Plasmodium yoelii [68], Anemia [69] and Drosophila [70], These enzymes are similar in size to the SERCAl- and SERCA2a-type Ca -ATPases from mammalian muscles, but based on their N- and C-terminal sequences they represent a distinct group. In spite of the wide philogenetic variations between them they all share a common N-term-inal sequence (MED) that differs from mammalian enzymes. None of the corresponding proteins were isolated and characterized. 

Paul There are two SERCA isoforms in smooth muscle, 2A and 2B, in roughly equal proportions. We suspect that there is a reason for this for example, one may be the housekeeping isoform found all over the place. 

Ca2+ is pumped into the SR stores by specific ATPases, the SERCA pumps. Three SERCA genes have been identified and several alternatively spliced gene products. In muscles SERCA1 is predominantly expressed in fast-twitch striated muscles and SERCA 2 isoforms are dominant in slow twitch, heart and smooth muscles, with SERCA2a in the former two, and SERCA2b predominant in smooth muscle and non-muscle cells. SERCA3 has a widespread distribution. 

Most work on the SR and diseased smooth muscle has concerned vascular smooth muscle in hypertensive animals, and bladders from animal models of outflow obstruction. The tools used to study SR function are mainly indirect, and include recording tension or intracellular [Ca2+] with fluorescent probes, measuring Ca2+ fluxes with 45Ca, and investigating the effects of drugs known to block SERCA or activate store release. More directly, some measurement of the activity of SERCA in microsomal preparations has been undertaken (e.g. Zderic et al 1996). 

Phospholamban is a protein that inhibits the SERCA pumps by decreasing their affinity for Ca2+. It can be phosphorylated by protein kinase A, for instance in response to /1-adrenoceptor activation, resulting in inhibition of its effects and enhanced SERCA activity. The effects of phospholamban on contraction depend on the relative importance of Ca2+ uptake or release in the smooth muscle in... 

Several of the proteins that mediate Ca2+ flow in and out of SR have been identified. Oxalate-facilitated Ca2+ uptake into the SR and in vitro biochemical studies of purified SR identified it as an ATP-driven Ca2+ pump (SERCA pump reviewed in Himpens et al 1995) that is inhibited by thapsigargin and cyclopiazonic acid and regulated, at least in some smooth muscles, by phosphorylation of phospholamban by cyclic nucleotide-activated protein kinase(s) (Karczewski et al 1998). 

The SERCA pump of many types of muscle is regulated by a protein called phospholam-bin, which binds to SERCA in both its cytosolic and its transmembrane regions, maintaining the pump in an inactivated state when in its non-phosphorylated form, but detaches from... 

Some sarco(endo)plasmic reticulum (SR) Ca +-ATPases (SERCA) are P-type ATPases that play a major role in muscle contraction-relaxation cycles and are responsible for transporting calcium into the lumen of the sarcoplasmic reticulum. Some definitions are useful in the discussion of Ca +-ATPases ... 

Schematic diagram of a cardiac muscle sarcomere, with sites of action of several drugs that alter contractility. Na+,K+ ATPase, the sodium pump, is the site of action of cardiac glycosides. NCX is the sodium, calcium exchanger. Cav-L is the voltage-gated, L-type calcium channel. SERCA (sarcoplasmic...

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