DOCSLIB.ORG

The Structure of the Ca -Atpase of Sarcoplasmic Reticulum

Total Page：16

File Type：pdf, Size：1020Kb

Download full-text PDF Read full-text
The Structure of the Ca -Atpase of Sarcoplasmic Reticulum Vol. 50 No. 2/2003 337–365 QUARTERLY Review The structure of the Ca2+-ATPase of sarcoplasmic reticulum. Anthony N. Martonosi1 and Slawomir Pikula2½ 1State University of New York, Upstate Medical University, College of Graduate Studies, Syracuse, New York, U.S.A.; 2M. Nencki Institute of Experimental Biology, Polish Academy of Sciences, Warszawa, Poland Received: 30 May, 2003; accepted: 02 June, 2003 Key words: calcium homeostasis, sarcoplasmic reticulum, calcium pump, calcium transport, excitation-contraction coupling, skeletal and cardiac muscles In this article the morphology of sarcoplasmic reticulum, classification of Ca2+-ATPase (SERCA) isoenzymes presented in this membrane system, as well as their topology will be reviewed. The focus is on the structure and interactions of Ca2+-ATPase determined by electron and X-ray crystallography, lamellar X-ray and neutron diffraction analysis of the profile structure of Ca2+-ATPase in sarcoplasmic reticulum multilayers. In addition, targeting of the Ca2+-ATPase to the sarcoplasmic reticulum is discussed. The classical studies of Heilbrunn and 1964) on the Ca2+ regulation of muscle con- Wierczinsky (1947), Ebashi (1961; 1962), traction by the sarcoplasmic reticulum (SR) Hasselbach (1961; 1963) and Weber (1959; set the stage for the exploration of the unique .This work was supported in part by grant No. 3 P04A 007 22 from the State Committee for Scientific Re- search (KBN, Poland). ½ Corresponding author: Slawomir Pikula, Department of Cellular Biochemistry, M. Nencki Institute of Experimental Biology, L. Pasteura 3, 02-093 Warszawa, Poland; tel.: (48 22) 659 8571 (ext. 347); fax: (48 22) 822 5342; e-mail: [email protected] Abbreviations: AMPPCP, 5¢-[beta,gamma-methylene]triphosphate; AMPPNP, adenosine 5¢-(beta,gamma-imino)triphosphate; BiP, immunoglobulin binding protein; caged ATP, P3-1(2-nitro)phenylethyladenosine-5¢-triphosphate; DHPR, dihydropyridine receptor; ER, endoplasmic reticulum; FITC, fluorescein-5¢-isothiocyanate; PLN, phospholamban; PMCA, plasma membrane Ca2+-ATPase; RyR, ryanodine receptor; SERCA, sarco(endo)plasmic reticulum Ca2+-ATPase; SR, sarcoplasmic reticulum; TG, thapsigargin; TNP-AMP, 2¢,3¢-O-(2,4,6-trinitrophenyl)AMP; 8-azido-TNP-ATP, 8-azido-2¢,3¢-O-(2,4,6-trinitrophenyl)ATP; V, vanadate; T-tubules, transverse tubules. 338 A.N. Martonosi and S. Pikula 2003 role of calcium in the regulation of a wide Mitchell et al., 1988). Among the SERCA range of metabolic processes and for the eluci- Ca2+-ATPase isoenzymes, the SERCA1 and dation of mechanisms by which cytoplasmic SERCA2a Ca2+ transport ATPase isoforms and intraorganellar Ca2+ concentrations are are evenly distributed throughout the free SR controlled in living cells. and most of the lateral sac, but are apparently excluded from the junctional SR. The SERCA2b isoform may be preferentially local- THE MORPHOLOGY OF ized near the T-SR junction. Detailed classifi- SARCOPLASMIC RETICULUM cation of SERCA isoforms is described in the next paragraph. The SR of skeletal muscle consists of two morphologically and functionally distinct re- gions: the junctional SR and the free SR (for CLASSIFICATION OF Ca2+-ATPase review see Peachey & Franzini-Armstrong, ISOENZYMES 1983). The junctional SR membrane contains the ryanodine receptor (RyR) Ca2+ channel The determination of the amino-acid se- with feetlike projections on its cytoplasmic quences of the sarcoplasmic reticulum Ca2+- surface that interact with the dihydropyridine ATPase (MacLennan et al., 1985), and of the receptor (DHPR) particles contained in the closely related Na+,K+-ATPase (Kawakami et junctional region of the T-tubules, forming the al., 1985; Shull et al., 1985) has opened a new T-SR (triad or dyad) junction. The T-SR junc- era in the analysis of ion transport mecha- tion is involved in the transmission of the ex- nisms. Since 1985 several large families of citatory stimulus from the surface membrane structurally related ion transport enzymes to the SR, causing Ca2+ release from the were discovered that are the products of dif- sarcoplasmic reticulum (Martonosi & Pikula, ferent genes. Within each family several iso- 2003). The free SR contains the Ca2+ trans- enzymes may be produced from a single gene port ATPase as its principal membrane com- product by alternative splicing. Our discus- ponent. It is usually divided into the lateral sion will concentrate on the Ca2+ transport sacs (cisternae), and the longitudinal tubules, ATPases that occur in the SR of muscle cells which differ in protein composition. The lat- of diverse fiber types and in the endoplasmic eral sacs contain electron-dense material in reticulum (ER) of nonmuscle cells. their lumen, which is attributed to the The sarco/endoplasmic reticulum Ca2+- lumenal Ca2+-binding proteins of SR (calse- ATPases of mammalian tissues can be divided questrin, calreticulin, high affinity Ca2+-bind- structurally into 3 main groups (SERCA1–3) ing proteins, etc.) that may serve as storage representing the products of different genes. sites for the accumulated Ca2+. The slender The SERCA1 gene (ATP2A1) produces two longitudinal tubules connect the lateral sacs isoforms of the Ca2+-ATPase, that are derived through the center of the sarcomere and by alternative splicing of the primary gene across the Z line; they contain little or no product (MacLennan et al., 1985; Brandl et al., calsequestrin. 1986). SERCA1a denotes the Ca2+-ATPase of Differential and sucrose gradient centri- adult fast-twitch skeletal muscle with glycine fugation permits the separation of the various at its C-terminus in the rabbit (Brandl et al., membrane elements into vesicular fractions 1987; Korczak et al., 1988), and alanine in the enriched in T-tubules, lateral sacs, and longi- chicken (Ohnoki & Martonosi, 1980; Karin et tudinal tubules, which differ in Ca2+ transport al., 1989). The C terminus of the lobster en- activity and protein composition (Caswell et zyme is apparently blocked (Ohnoki & al., 1988; Chu et al., 1988; Costello et al., 1988; Martonosi, 1980). SERCA1b is the alterna- Vol. 50 Calcium pump of sarcoplasmic reticulum 339 tively spliced neonatal form of SERCA1, in a sorting signal for retention of the enzyme in which the glycine at the C-terminus is re- the endoplasmic reticulum (Burk et al., 1989). placed by the alternative sequence -Asp-Pro- Sequences of SERCA type Ca2+-ATPases Glu-Asp-Glu-Arg-Arg-Lys (Brandl et al., 1986; were also obtained from Plasmodium yoelii 1987). The gene encoding SERCA1 is on hu- (Murakami et al., 1990), Artemia (Palmero et man chromosome 16 (MacLennan et al., al., 1989), and Drosophila (Magyar et al., 1987). A selective defect in its expression is 1995). These enzymes are similar in size to the cause of some forms of Brody’s disease SERCA type Ca2+-ATPases from mammalian (MacLennan, 2000). muscles, but based on their N- and C-terminal The SERCA2 gene (ATP2A2) also produces sequences they represent a distinct group. In at least two isoforms that are tissue specific. spite of the wide phylogenetic variations be- SERCA2a is the principal form of the tween them, they all share a common N-ter- Ca2+-ATPase in adult slow-twitch skeletal and minal sequence (Met-Glu-Asp) that differs cardiac muscles and in neonatal skeletal mus- from mammalian enzymes. cles (Barndl et al., 1986; MacLennan et al., The molecular masses of all SERCA type 1987; Lytton et al., 1988; 1992; Wu et al., Ca2+ transport ATPases of muscle are close to 1995; Verboomen et al., 1995). It is also ex- 110 kDa. Their N-terminal sequences are simi- pressed at much lower levels in nonmuscle lar: Met-Glu-X(Ala, Asn, Glu, Asp)-X (Ala, Gly, cells (Wu et al., 1995). Its C-terminus is Ile). The Met-Glu-X-X sequence serves as sig- Pro-Ala-Ile-Leu-Glu. SERCA2b is an alterna- nal for the acetylation of N-terminal tively spliced product of the same gene methionine both in soluble and in membrane (Gunteski-Humblin et al., 1988; Lytton et al., proteins (Tong, 1977; 1980). 1989). It is located primarily in nonmuscle tis- sues and in smooth muscles, where it serves as the major intracellular Ca2+ pump. THE PREDICTED TOPOLOGY OF SERCA2b is characterized by a long Ca2+-ATPases C-terminal extension of 50 amino acid resi- dues ending in Trp-Ser (Gunteski-Humblin et Combining structural and biochemical infor- al., 1988; Lytton et al., 1988; 1989). The gene mation, MacLennan and his colleagues con- for both forms of SERCA2 is located on hu- structed a hypothetical model of the tertiary man chromosome 12 (MacLennan et al., structure of Ca2+-ATPase (MacLennan et al., 1987). Its expression is not affected in Brody’s 1985; 1997) that had interesting mechanistic disease, suggesting that the two major forms implications (Fig. 1), and was largely con- of SR Ca2+-ATPases are independently regu- firmed by recent structural data (MacLennan lated. & Green, 2000; Toyoshima et al., 2000; Green SERCA3 is encoded by the ATP2A3 gene et al., 2002; Toyoshima & Nomura, 2002; (Dode et al., 1996). It is broadly distributed in Toyoshima et al., 2003). The structure was di- skeletal muscle, heart, uterus, and in a variety vided into three major parts, designated as of nonmuscle cells (Burk et al., 1989; Wuytack the cytoplasmic headpiece, the stalk domain et al., 1995; Dode et al., 1996; Kovacs et al., and the transmembrane domain. Only short 2001). The mRNA levels are particularly high loops were assumed to be exposed on the in intestine, lung and spleen, while it is very luminal side of the membrane. low in liver, testes, kidney and pancreas. In More than half of the total mass of the the muscle tissue SERCA3 may be confined ATPase molecule is exposed on the cytoplas- primarily to nonmuscle cells (endothelial mic surface of the membrane, forming the cy- cells, etc.). The C-terminus of SERCA3 is toplasmic head piece (Fig. 1). The headpiece Asp-Gly-Lys-Lys-Asp-Leu-Lys; it may serve as contains six subdomains: the N-terminal re- 340 A.N.
Load more

Recommended publications
  • Plasma Membrane Ca2+–Atpase in Rat and Human Odontoblasts Mediates Dentin Mineralization
    biomolecules Article Plasma Membrane Ca2+–ATPase in Rat and Human Odontoblasts Mediates Dentin Mineralization Maki Kimura 1,†, Hiroyuki Mochizuki 1,†, Ryouichi Satou 2, Miyu Iwasaki 2, Eitoyo Kokubu 3, Kyosuke Kono 1, Sachie Nomura 1, Takeshi Sakurai 1, Hidetaka Kuroda 1,4,† and Yoshiyuki Shibukawa 1,*,† 1 Department of Physiology, Tokyo Dental College, 2-9-18, Kanda-Misaki-cho, Chiyoda-ku, Tokyo 101-0061, Japan; [email protected] (M.K.); [email protected] (H.M.); [email protected] (K.K.); [email protected] (S.N.); [email protected] (T.S.); [email protected] (H.K.) 2 Department of Epidemiology and Public Health, Tokyo Dental College, Chiyodaku, Tokyo 101-0061, Japan; [email protected] (R.S.); [email protected] (M.I.) 3 Department of Microbiology, Tokyo Dental College, Chiyodaku, Tokyo 101-0061, Japan; [email protected] 4 Department of Dental Anesthesiology, Kanagawa Dental University, 1-23, Ogawacho, Kanagawa, Yokosuka-shi 238-8570, Japan * Correspondence: [email protected] † These authors contributed equally to this study. Abstract: Intracellular Ca2+ signaling engendered by Ca2+ influx and mobilization in odontoblasts is critical for dentinogenesis induced by multiple stimuli at the dentin surface. Increased Ca2+ is exported by the Na+–Ca2+ exchanger (NCX) and plasma membrane Ca2+–ATPase (PMCA) to Citation: Kimura, M.; Mochizuki, H.; maintain Ca2+ homeostasis. We previously demonstrated a functional coupling between Ca2+ Satou, R.; Iwasaki, M.; Kokubu, E.; extrusion by NCX and its influx through transient receptor potential channels in odontoblasts. Kono, K.; Nomura, S.; Sakurai, T.; Although the presence of PMCA in odontoblasts has been previously described, steady-state levels of Kuroda, H.; Shibukawa, Y.
    [Show full text]
  • Molecular Regulation and Physiology of the H ,K -Atpases in Kidney
    Molecular Regulation and Physiology of the H؉,K؉-ATPases in Kidney Juan Codina and Thomas D. DuBose Jr Two H؉,K؉-adenosine triphosphatase (ATPase) proteins participate in K؉ absorption and ؉ ؉ ؉ H secretion in the renal medulla. Both the gastric (HK␣1) and colonic (HK␣2)H,K - ATPases have been localized and characterized by a number of techniques, and are known to be highly regulated in response to acid-base and electrolyte disturbances. Both ATPases are dimers of composition ␣/␤ that localize to the apical membrane and both interact with the tetraspanin protein CD63. Although CD63 interacts with the carboxy-terminus of the subunit of the colonic H؉,K؉-ATPase, it interacts with the ␤-subunit of the gastric-␣ H؉,K؉-ATPase. Pharmacologically, both ATPases are distinct; for example, the gastric H؉,K؉-ATPase is inhibited by Sch-28080, but the colonic H؉,K؉-ATPase is inhibited by .ouabain (a classic inhibitor of the Na؉-pump) and is completely insensitive to Sch-28080 The ␣-subunit of the colonic H؉,K؉-ATPase is the only subunit of the X؉,K؉-ATPase superfamily that has 3 different splice variants that emerge by deletion or elongation of the amino-terminus. The messenger RNA and protein of one of these splice variants (HK␣2C)is specifically up-regulated in newborn rats and becomes undetectable in adult rats. There- fore, HK␣2, in addition to its role in potassium and acid-base homeostasis, appears to play a significant role in early growth and development. Finally, because chronic hypokalemia appears to be the most potent stimulus for upregulation of HK␣2, we propose that the HK␣2 participates importantly in the maintenance of chronic metabolic alkalosis.
    [Show full text]
  • SERCA in Genesis of Arrhythmias: What We Already Know and What Is New?
    Review 43 SERCA in genesis of arrhythmias: what we already know and what is new? Nilüfer Erkasap Department of Physiology, Medical Faculty, Eskiflehir Osmangazi University, Eskiflehir, Turkey ABSTRACT This review mainly focuses on the structure, function of the sarco(endo)plasmic reticulum calcium pump (SERCA) and its role in genesis of arrhythmias. SERCA is a membrane protein that belongs to the family of P-type ion translocating ATPases and pumps free cytosolic calcium into intracellular stores. Active transport of Ca2+ is achieved, according to the E1-E2 model, changing of SERCA structure by Ca2+. The affinity of Ca2+ -binding sites varies from high (E1) to low (E2). Three different SERCA genes were identified-SERCA1, SERCA2, and SERCA3. SERCA is mainly represented by the SERCA2a isoform in the heart. In heart muscle, during systole, depolarization triggers the release of Ca2+ from the sarcoplasmic reticulum (SR) and starts contraction. During diastole, muscle relaxation occurs as Ca2+ is again removed from cytosol, predominantly by accumulation into SR via the action of SERCA2a. The main regulator of SERCA2a is phospholamban and another regulator proteolipid of SERCA is sarcolipin. There are a lot of studies on the effect of decreased and/or increased SERCA activity in genesis of arrhythmia. Actually both decrease and increase of SERCA activity in the heart result in some pathological mechanisms such as heart failure and arrhythmia. (Anadolu Kardiyol Derg 2007: 7 Suppl 1; 43-6) Key words: sarco(endo)plasmic reticulum, SERCA, arrhythmia, calcium channels Introduction from cytosol, predominantly by accumulation into sarcoplasmic reticulum via the action of sarco(endo)plasmic reticulum Cardiac physiology is a major area of research in basic and Ca ATPase (SERCA).
    [Show full text]
  • Endoplasmic Reticulum Potassium–Hydrogen Exchanger and Small
    Research Article 625 Endoplasmic reticulum potassium–hydrogen exchanger and small conductance calcium-activated potassium channel activities are essential for ER calcium uptake in neurons and cardiomyocytes Malle Kuum1,2,3, Vladimir Veksler2,3, Joanna Liiv1, Renee Ventura-Clapier2,3 and Allen Kaasik1,* 1Department of Pharmacology, Centre of Excellence for Translational Medicine, University of Tartu, Ravila 19, Tartu EE-51014, Estonia 2INSERM, U-769, 5, rue Jean-Baptiste Clement, Chaˆtenay-Malabry F-92296, France 3Universite´ Paris-Sud, 5, rue Jean-Baptiste Clement, Chaˆtenay-Malabry F-92296, France *Author for correspondence ([email protected]) Accepted 12 September 2011 Journal of Cell Science 125, 625–633 ß 2012. Published by The Company of Biologists Ltd doi: 10.1242/jcs.090126 Summary Calcium pumping into the endoplasmic reticulum (ER) lumen is thought to be coupled to a countertransport of protons through sarcoplasmic/endoplasmic reticulum calcium ATPase (SERCA) and the members of the ClC family of chloride channels. However, pH in the ER lumen remains neutral, which suggests a mechanism responsible for proton re-entry. We studied whether cation–proton exchangers could act as routes for such a re-entry. ER Ca2+ uptake was measured in permeabilized immortalized hypothalamic neurons, primary rat cortical neurons and mouse cardiac fibers. Replacement of K+ in the uptake solution with Na+ or tetraethylammonium led to a strong inhibition of Ca2+ uptake in neurons and cardiomyocytes. Furthermore, inhibitors of the potassium–proton exchanger (quinine or propranolol) but not of the sodium–proton exchanger reduced ER Ca2+ uptake by 56–82%. Externally added nigericin, a potassium– + proton exchanger, attenuated the inhibitory effect of propranolol.
    [Show full text]
  • Crystal Structure of the Calcium Pump of Sarcoplasmic Reticulum at 2.6 AÊ Resolution
    articles Crystal structure of the calcium pump of sarcoplasmic reticulum at 2.6 AÊ resolution Chikashi Toyoshima*², Masayoshi Nakasako*²³, Hiromi Nomura* & Haruo Ogawa* * Institute of Molecular and Cellular Biosciences, The University of Tokyo, Bunkyo-ku, Tokyo 113-0032, Japan ² The Harima Institute, The Institute of Physical and Chemical Research, Sayo-gun, Hyo-go 679-5143, Japan ³ PRESTO, Japan Science and Technology Corporation, Kawaguchi 332-0012, Japan ............................................................................................................................................................................................................................................................................ Calcium ATPase is a member of the P-type ATPases that transport ions across the membrane against a concentration gradient. Here we have solved the crystal structure of the calcium ATPase of skeletal muscle sarcoplasmic reticulum (SERCA1a) at 2.6 AÊ resolution with two calcium ions bound in the transmembrane domain, which comprises ten a-helices. The two calcium ions are located side by side and are surrounded by four transmembrane helices, two of which are unwound for ef®cient coordination geometry. The cytoplasmic region consists of three well separated domains, with the phosphorylation site in the central catalytic domain and the adenosine-binding site on another domain. The phosphorylation domain has the same fold as haloacid dehalogenase. Comparison with a low-resolution electron density map of the enzyme in the absence
    [Show full text]
  • Clinical Significance of P‑Class Pumps in Cancer (Review)
    ONCOLOGY LETTERS 22: 658, 2021 Clinical significance of P‑class pumps in cancer (Review) SOPHIA C. THEMISTOCLEOUS1*, ANDREAS YIALLOURIS1*, CONSTANTINOS TSIOUTIS1, APOSTOLOS ZARAVINOS2,3, ELIZABETH O. JOHNSON1 and IOANNIS PATRIKIOS1 1Department of Medicine, School of Medicine; 2Department of Life Sciences, School of Sciences, European University Cyprus, 2404 Nicosia, Cyprus; 3College of Medicine, Member of Qatar University Health, Qatar University, 2713 Doha, Qatar Received January 25, 2021; Accepted Apri 12, 2021 DOI: 10.3892/ol.2021.12919 Abstract. P‑class pumps are specific ion transporters involved Contents in maintaining intracellular/extracellular ion homeostasis, gene transcription, and cell proliferation and migration in all 1. Introduction eukaryotic cells. The present review aimed to evaluate the 2. Methodology role of P‑type pumps [Na+/K+ ATPase (NKA), H+/K+ ATPase 3. NKA (HKA) and Ca2+‑ATPase] in cancer cells across three fronts, 4. SERCA pump namely structure, function and genetic expression. It has 5. HKA been shown that administration of specific P‑class pumps 6. Clinical studies of P‑class pump modulators inhibitors can have different effects by: i) Altering pump func‑ 7. Concluding remarks and future perspectives tion; ii) inhibiting cell proliferation; iii) inducing apoptosis; iv) modifying metabolic pathways; and v) induce sensitivity to chemotherapy and lead to antitumor effects. For example, 1. Introduction the NKA β2 subunit can be downregulated by gemcitabine, resulting in increased apoptosis of cancer cells. The sarco‑ The movement of ions across a biological membrane is a endoplasmic reticulum calcium ATPase can be inhibited by crucial physiological process necessary for maintaining thapsigargin resulting in decreased prostate tumor volume, cellular homeostasis.
    [Show full text]
  • Specific Copb Transporter: Revising P1B-Type Atpase Classification
    + Cu -specific CopB transporter: Revising P1B-type ATPase classification Rahul Purohita,b, Matthew O. Rossa,b, Sharon Bateluc, April Kusowskic,d, Timothy L. Stemmlerc,d, Brian M. Hoffmana,b, and Amy C. Rosenzweiga,b,1 aDepartment of Molecular Biosciences, Northwestern University, Evanston, IL 60208; bDepartment of Chemistry, Northwestern University, Evanston, IL 60208; cDepartment of Pharmaceutical Sciences, Wayne State University, Detroit, MI 48201; and dSchool of Medicine, Wayne State University, Detroit, MI 48201 Contributed by Amy C. Rosenzweig, January 12, 2018 (sent for review December 14, 2017; reviewed by Megan M. McEvoy and Gabriele Meloni) The copper-transporting P1B-ATPases, which play a key role in cellu- metal specificities of the P1B-5 (PCP motif), P1B-6 (SCA motif), lar copper homeostasis, have been divided traditionally into two and P1B-7-ATPases (CSC motif) remain unclear, although some 2+ 2+ subfamilies, the P1B-1-ATPases or CopAs and the P1B-3-ATPases or evidence links the P1B-5-ATPases to Ni and Fe (20, 21). The + CopBs. CopAs selectively export Cu whereas previous studies and remaining two groups are the copper transporters. The P1B-1- + bioinformatic analyses have suggested that CopBs are specific for ATPases, which include ATP7A and ATP7B, transport Cu 2+ 2+ Cu export. Biochemical and spectroscopic characterization of (9, 22), whereas the P1B-3-ATPases are proposed to transport Cu Sphaerobacter thermophilus CopB (StCopB) show that, while it does (23, 24). These two subfamilies differ from one another in several 2+ bind Cu , the binding site is not the prototypical P1B-ATPase trans- ways. First, the TM helix 4 motif is CPC in the P1B-1-ATPases and membrane site and does not involve sulfur coordination as proposed CPH in the P1B-3-ATPases.
    [Show full text]
  • Ca2+-Atpase Molecules As a Calcium-Sensitive Membrane-Endoskeleton of Sarcoplasmic Reticulum
    International Journal of Molecular Sciences Article Ca2+-ATPase Molecules as a Calcium-Sensitive Membrane-Endoskeleton of Sarcoplasmic Reticulum Jun Nakamura 1,*, Yuusuke Maruyama 1, Genichi Tajima 2, Yuto Komeiji 1, Makiko Suwa 3 and Chikara Sato 1,* 1 Health and Medical Research Institute, National Institute of Advanced Industrial Science and Technology (AIST), Central 6, 1-1-1 Higashi, Tsukuba, Ibaraki 305-8566, Japan; [email protected] (Y.M.); [email protected] (Y.K.) 2 Institute for Excellence in Higher Education, Tohoku University, 41 Kawauchi, Aoba-ku, Sendai, Miyagi 980-8576, Japan; [email protected] 3 Biological Science Course, Graduate School of Science and Engineering, Aoyama Gakuin University, 5-10-1 Fuchinobe, Chuou-ku, Sagamihara, Kanagawa 252-5258, Japan; [email protected] * Correspondence: [email protected] (J.N.); [email protected] (C.S.) Abstract: The Ca2+-transport ATPase of sarcoplasmic reticulum (SR) is an integral, transmembrane protein. It sequesters cytoplasmic calcium ions released from SR during muscle contraction, and causes muscle relaxation. Based on negative staining and transmission electron microscopy of SR vesicles isolated from rabbit skeletal muscle, we propose that the ATPase molecules might also be a calcium-sensitive membrane-endoskeleton. Under conditions when the ATPase molecules scarcely transport Ca2+, i.e., in the presence of ATP and ≤ 0.9 nM Ca2+, some of the ATPase particles on the SR vesicle surface gathered to form tetramers. The tetramers crystallized into a cylindrical helical array in some vesicles and probably resulted in the elongated protrusion that extended from some round SRs.
    [Show full text]
  • ATP Synthase: Structure,Abstract: Functionlet F Denote a Eld and and Let Inhibitionv Denote a Vector Space Over F with Nite Positive Dimension
    Spec. Matrices 2019; 7:1–19 Research Article Open Access Kazumasa Nomura* and Paul Terwilliger BioMol Concepts 2019; 10: 1–10 Self-dual Leonard pairs Research Article Open Access https://doi.org/10.1515/spma-2019-0001 Prashant Neupane*, Sudina Bhuju, Nita Thapa,Received Hitesh May 8, 2018; Kumar accepted Bhattarai September 22, 2018 ATP Synthase: Structure,Abstract: FunctionLet F denote a eld and and let InhibitionV denote a vector space over F with nite positive dimension. Consider a pair A, A∗ of diagonalizable F-linear maps on V, each of which acts on an eigenbasis for the other one in an irreducible tridiagonal fashion. Such a pair is called a Leonard pair. We consider the self-dual case in which https://doi.org/10.1515/bmc-2019-0001 there exists an automorphism of the endomorphism algebra of V that swaps A and A∗. Such an automorphism phosphate (Pi), along with considerable release of energy. received September 18, 2018; accepted December 21, 2018. is unique, and called the duality A A∗. In the present paper we give a comprehensive description of this ADP can absorb energy and regain↔ the group to regenerate duality. In particular, we display an invertible F-linear map T on V such that the map X TXT− is the duality Abstract: Oxidative phosphorylation is carried out by an ATP molecule to maintain constant ATP concentration. → A A∗. We express T as a polynomial in A and A∗. We describe how T acts on ags, decompositions, five complexes, which are the sites for electron transport↔ Other than supporting almost all the cellular and ATP synthesis.
    [Show full text]
  • Gastric H,K-Atpase As a Drug Target
    UCLA UCLA Previously Published Works Title Gastric H,K-ATPase as a drug target Permalink https://escholarship.org/uc/item/1g5606x9 Journal Digestive Diseases and Sciences, 51(5) ISSN 0163-2116 Authors Shin, Jai M Sachs, G Publication Date 2006-05-01 Peer reviewed eScholarship.org Powered by the California Digital Library University of California The Gastric H,K-ATPase as a Drug Target Jai Moo Shin and George Sachs* Department of Physiology and Medicine, University of California at Los Angeles, and VA Greater Los Angeles Healthcare System, Los Angeles, California, CA90073, USA * To whom correspondence should be addressed: at Membrane Biology Laboratory, VA Greater Los Angeles Healthcare System, 11301 Wilshire Blvd., Bldg. 113, Rm. 324, Los Angeles, CA 90073 Tel: (310) 268-4672 Fax: (310) 312-9478 e-mail: [email protected] 1 Introduction Gastric acid is secreted by parietal cells in the stomach. These have two known acid stimulatory receptors the H2-receptor and the muscarinic M3 receptor. Gastrin, the major endocrine activator of acid secretion, exerts its action via release of histamine from the ECL cell as does pituitary adenylate cyclase activating peptide (PACAP), a neural mediator of activation of acid secretion. Antagonists of the former two stimulants inhibit gastric acid secretion. Cholinergic receptor antagonists have many side effects and are relatively weak inhibitors at therapeutic doses as compared toH2-receptor antagonists. These drugs were widely developed in the 1970’s and 1980’s and became the first really useful medications for healing of peptic ulcers. However, although good for healing peptic ulcers, they were less effective in treatment of erosive esophagitis.
    [Show full text]
  • Plasma Membrane Ca2+ Atpase Isoform 4 (PMCA4) Has an Important Role in Numerous Hallmarks of Pancreatic Cancer
    cancers Article Plasma Membrane Ca2+ ATPase Isoform 4 (PMCA4) Has an Important Role in Numerous Hallmarks of Pancreatic Cancer Pishyaporn Sritangos 1 , Eduardo Pena Alarcon 1, Andrew D. James 2, Ahlam Sultan 3, Daniel A. Richardson 1 and Jason I. E. Bruce 1,* 1 Division of Cancer Sciences, School of Medical Sciences, Faculty of Biology, Medicine and Health, University of Manchester, Manchester M13 9PT, UK; [email protected] (P.S.); [email protected] (E.P.A.); [email protected] (D.A.R.) 2 Department of Biology, University of York, Heslington, York YO10 5DD, UK; [email protected] 3 Department of Pharmaceutical Science, College of Pharmacy, Princess Nourah Bint Abdulrahman University, Riyadh, Saudi Arabia; [email protected] * Correspondence: [email protected]; Tel.:+44-16-12-75-54-84 Received: 13 November 2019; Accepted: 10 January 2020; Published: 16 January 2020 Abstract: Pancreatic ductal adenocarcinoma (PDAC) is largely resistant to standard treatments leading to poor patient survival. The expression of plasma membrane calcium ATPase-4 (PMCA4) is reported to modulate key cancer hallmarks including cell migration, growth, and apoptotic resistance. Data-mining revealed that PMCA4 was over-expressed in pancreatic ductal adenocarcinoma (PDAC) tumors which correlated with poor patient survival. Western blot and RT-qPCR revealed that MIA PaCa-2 cells almost exclusively express PMCA4 making these a suitable cellular model of PDAC with poor patient survival. Knockdown of PMCA4 in MIA PaCa-2 cells (using siRNA) reduced cytosolic 2+ 2+ Ca ([Ca ]i) clearance, cell migration, and sensitized cells to apoptosis, without affecting cell growth.
    [Show full text]
  • Inhibin, Activin, Follistatin and FSH Serum Levels and Testicular
    REPRODUCTIONRESEARCH Expression of Atp8b3 in murine testis and its characterization as a testis specific P-type ATPase Eun-Yeung Gong, Eunsook Park, Hyun Joo Lee and Keesook Lee School of Biological Sciences and Technology, Hormone Research Center, Chonnam National University, Gwangju 500-757, Republic of Korea Correspondence should be addressed to K Lee; Email: [email protected] Abstract Spermatogenesis is a complex process that produces haploid motile sperms from diploid spermatogonia through dramatic morphological and biochemical changes. P-type ATPases, which support a variety of cellular processes, have been shown to play a role in the functioning of sperm. In this study, we isolated one putative androgen-regulated gene, which is the previously reported sperm-specific aminophospholipid transporter (Atp8b3, previously known as Saplt), and explored its expression pattern in murine testis and its biochemical characteristics as a P-type ATPase. Atp8b3 is exclusively expressed in the testis and its expression is developmentally regulated during testicular development. Immunohistochemistry of the testis reveals that Atp8b3 is expressed only in germ cells, especially haploid spermatids, and the protein is localized in developing acrosomes. As expected, from its primary amino acid sequence, ATP8B3 has an ATPase activity and is phosphorylated by an ATP-producing acylphosphate intermediate, which is a signature property of the P-Type ATPases. Together, ATP8B3 may play a role in acrosome development and/or in sperm function during fertilization. Reproduction (2009) 137 345–351 Introduction the removal of testosterone by hypophysectomy or ethane dimethanesulfonate (EDS) treatment in rats leads to the Spermatogenesis is one of most complex processes of cell failure of spermatogenesis (Russell & Clermont 1977, differentiation in animals, in which diploid spermatogo- Bartlett et al.
    [Show full text]