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Cardiac Sarcoplasmic Reticulum Ca2+‐ATPase

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Abstract

The sections in this article are:

1 Structure of the Ca2+‐ATPase
1.1 Structure of Cardiac Sarcoplasmic Reticulum
1.2 Isolation and Characterization of Cardiac Sarcoplasmic Reticulum
2 Function of Ca2+‐ATPase
2.1 Ca2+ Pumping Function
2.2 Mechanism of Ca2+‐ATPase Activity
2.3 Regulation of Ca2+‐ATPase Activity
3 Structure and Function of Ca2+‐ATPase
3.1 Primary Sequences and Structural Models for Ca2+‐ATPases
3.2 Chemical Modifications of the Ca2+‐ATPase
3.3 Site‐Directed Mutagenesis of Ca2+‐ATPase
3.4 Ca2+‐ATPase Isoform Chimeras
4 Regulation of Ca2+‐ATPase by Phospholamban
4.1 Structure of Phospholamban
4.2 Function of Phospholamban
4.3 Interaction Between Ca2+‐ATPase and Phospholamban
4.4 Physiological Relevance of Phospholamban‐Ca2+‐ATPase System
5 Regulation of Ca2+‐ATPase and Phospholamban Genes
5.1 Structure of the Ca2+‐ATPase Gene
5.2 Transcriptional Regulation of the Ca2+‐ATPase Gene
5.3 Structure of the Phospholamban Gene
5.4 Transcriptional Regulation of the Phospholamban Gene
Figure 1. Figure 1.

Schematic model of the ultrastructure of the cardiac cell. Contractile proteins are arranged in a regular array of thick and thin filaments. The A‐band represents the region of the sarcomere occupied by the thick filaments. Thin filaments extend variable distances into the A‐band, from either side. The I‐band represents the region of the sarcomere occupied excessively by thin filaments, which extend toward the center of the sarcomere from the Z‐lines. The sarcomere, the functional unit of the contractile apparatus, is defined as the region between a pair of Z‐lines, and contains two half I‐bands and one A‐band. The sarcoplasmic reticulum consists of the longitudinal reticulum and the terminal cisternae, which abut the transverse tubular system (T‐tubule). The T‐tubule is a sarcolemmal invagination, so that the lumen of the T‐tubules is continuous with the extracellular space. Slow Ca2+ channels in the T‐tubule are believed to be associated with the Ca2+ release channel in the junctional face of the terminal cisternae. In the lumen of the terminal cisternae, Ca2+‐binding proteins, calsequestrin, calreticulin, and histidine‐rich Ca2+ binding protein also exist. In the longitudinal reticulum, Ca2+‐ATPase and phospholamban exist in the membrane, and glycoproteins of 53 kDa and 160 kDa are located in the lumen.

Figure 2. Figure 2.

The reaction cycle. Steps involved in the process of ATP hydrolysis and Ca2+ transport by the sarcoplasmic reticulum Ca2+ ATPase. See text for details.

Figure 3. Figure 3.

Secondary structural model of the Ca2+‐ATPase molecule. This structural diagram is based on predictions of domain structure and a hydropathy plot . The bulk of the protein consists of a cytoplasmic globular headpiece structure and ten membrane‐spanning segments (M1–M10), which are connected via a stalk‐like cluster of α‐helices. The large globular cytoplasmic part is composed of three domains: the β‐strand domain, between segments M2 and M3; the phosphorylation domain, attached to segment M4 at one end and to the nucleotide‐binding domain at the other. The nucleotide binding domain runs into a hinge domain, which is attached to segment M5. The folding of the cytoplasmic structure is indicated schematically in accordance with the general principles established for antiparallel or parallel β‐sheet domains . The α‐helical sequence and the β‐sheet sequences are shown by cylinders and arrows, respectively. The numbers at the top and bottom of each transmembrane helix indicate the amino acid positions at each end of these helices.

Figure 4. Figure 4.

False‐color stereo shaded solid rendering of a section of a three‐dimensional reconstruction of the Z‐band from unstimulated rat soleus muscle. This 14 nm‐thick longitudinal section shows the interdigitating axial filaments and the cross‐connecting Z‐filament array. Axial filaments enter the Z‐band from the top (yellow) and bottom (orange) of the figure. The filaments are joined together by cross‐connecting Z‐filaments (blue), which also connect to the filamentous relaxed interconnecting body or Z‐RIB (red). In the I‐band near the top and bottom of the figure, some connections run directly between the axial filaments (magenta). Amorphous material (gray) obscures the filaments near the bottom corners of this section; scale bar = 10 nm).

Reprinted by permission of Rockefeller University Press
Figure 5. Figure 5.

Enzymatically dissociated left ventricular myocytes from adult dog (A) and rat (B). Bisbenzimide staining. A and B: bars = 100 μm.

Figure 6. Figure 6.

Photomicrographs showing mitotic figures detected in the ventricular myocardium of the human (A, B, D, E, and F) and rat (C) heart. The light microscopic mitotic images in panels A and B were found in a patient who died as a result of an extensive acute myocardial infarction. C illustrates by light microscopy a mitotic figure in a severely anemic adult rat with ventricular dysfunction. The mitotic images shown by confocal microscopy in D‐F were detected in a patient affected by end‐stage dilated cardiomyopathy. Large field area, illustrating by propidium iodide labeling only (green fluorescence; D) and by a combination of propidium iodide and α‐sarcomeric actin antibody staining of the myocyte cytoplasm (red fluorescence; E), a myocyte nucleus in metaphase (arrowhead) and a myocyte at completion of cytokinesis (arrow). Myocyte cytokinesis is shown at higher magnification in F. A, B, and D‐F: Paraffin‐embedded sections stained by hematoxylin and eosin (A and B) and propidium iodide (D‐F) and α‐sarcomeric actin (E and F). C: Semithin section of plastic‐embedded tissue stained by toluidine blue. A‐F: bars correspond to 10 μm.

D‐F: reproduced from ; copyright © 1998 National Academy of Sciences, USA
Figure 7. Figure 7.

Frozen sections of ventricular myocardium showing bromodeoxyuridine (BrdU) labeling of a myocyte nucleus after coronary artery narrowing. (A) BrdU labeling by immunofluorescence; (B): the same field shown by phase‐contrast microscopy and bisbenzimide H33258 fluorescence. A and B: bars = 10 μm.

Figure 8. Figure 8.

Semithin sections of plastic‐embedded rat ventricular myocardium after coronary artery narrowing (A) and coronary artery occlusion (B) showing mitotic figures. A: Methylene blue and safranin staining; B: Toluidine blue staining. A and B: bars = 10 μm.

Figure 9. Figure 9.

Peptide sequence alignment of mouse and human cardiac connexins. The color bar code at the top of the alignment indicates the degree of homology among all cardiac connexins, where red indicates identity, dark blue very low homology, and intermediate colors moderate similarity. (Alignment provided by Ms. M. Urban, using Clustal method with PAM 100 residue weight table, Lasergene program, DNASTAR Inc.) Regions corresponding to membrane‐spanning domains M1, M2, M3, M4 in Figure B are indicated.

Figure 10. Figure 10.

Propagation of slow intercellular calcium waves between wild‐type (A) and Cx43‐null (B) neonatal mouse cardiac myocytes loaded with an intracellular calcium indicator (Indo‐1AM) and imaged with real‐time confocal microscopy (Nikon RCM 8000). The mechanical stimulation of a single myocyte in culture (cell A, red arrow, uper left frames) initiates the propagation of the calcium wave captured in the pseudocolored display at 5 sec intervals (green: low Ca2+; red: high Ca2+). Graphical representations of the phenomenon as a function of time are shown to the right of the photographs; arrows indicate the moment of the stimulation. Note that the absence of Cx43 expression does not prevent the communication of the calcium signal, but reduces the efficacy of calcium wave spread, which extends to fewer cells per field than in wild‐type myocytes.

Figure 11. Figure 11.

Regulated expression of diphtheria toxin A in the hearts of transgenic mice results in spontaneous and inducible arrhythmias in vivo and in isolated‐perfused hearts. (A). Rhythm strip from awake, freely mobile transgenic mouse using a telemetric system shows a run of ventricular tachycardia. (B). Rapid ventricular tachycardia induced in an isolated‐perfused heart from a similar transgenic mouse. (C). Optical mapping showing normal activation profile (left panel) and perturbed epicardial activation (right panel) in a myopathic, transgenic heart.

From Lee et al. (1998)
Figure 12. Figure 12.

Effects of phospholamban mutations on apparent Ca2+ affinity of SERCA2 and location of residues in phospholamban that affect interaction with SERCA2 in cytoplasmic and transmembrane domains. Top: Ca2+‐dependence of Ca2+ uptake rates for SERCA2 were measured in the presence of coexpressed phospholamban (PLN) (solid line), and in the absence of phospholamban (dashed line). Ca2+‐dependence of Ca2+ uptake for SERCA2 coexpressed with wild‐type and mutant PLN is classified into three types in accordance with the extent of inhibitory actions on Ca2+ uptake rate. Wild‐type and no change phospholamban mutants lower the Ca2+ affinity for SERCA2 by about 0.34 pCa units (open circles), loss of function mutants do not alter the Ca2+ affinity for SERCA2 (red circles), and gain of function mutants diminish apparent Ca2+ affinity by up to 1 pCa unit, enhancing the inhibitory effect on Ca2+ uptake at low Ca2+ concentrations (green circles). Bottom: Location of phospholamban mutations that affect apparent Ca2+ affinity for SERCA2, presented in an α‐helical wheel configuration for both domain Ia and domain II. Each amino acid is classified into three types in accordance with the loss (red circles), gain (green circles), or no change (open circles) on inhibitory function. Phospholamban is abbreviated as PLN.

Figure 13. Figure 13.

Excitation of the isolated human heart. Isochrone map of the ventricular activation of an isolated human heart, based on measurements at 870 intramural electrode terminals. The horizontal planes into which the multi‐electrodes were inserted, and into which the heart was sectioned, are depicted. Each color represents a 5‐msec interval. Zero time is the beginning of the left ventricular cavity potential. White areas indicate either fatty tissue or parts of the myocardium for which no data are available. RA = right atrial cavity; LA = left atrial cavity; Ao = aorta; LV = left ventricular cavity; RV = right ventricular cavity; MV = mitral valve.

Reproduced with permission from reference
Figure 14. Figure 14.

Reversal of unidirectional block to bidirectional conduction by partial cell‐to‐cell uncoupling. Unidirectional block in patterned cell cultures (A) is produced by current‐to‐load mismatch at a geometrical expansion—i.e., an insertion of a small cell strand into a large tissue mass. The degree of electrical cell‐to‐cell coupling in the large area can be changed by application of a blocking agent (palmitoleic acid, 10 μmol/liter) through local superfusion (yellow area in B). During control (C) excitation (red) after stimulation of the strand is observed only in the small strand, while the unidirectional block leaves the large area at rest (blue), because of current‐to‐load mismatch at the expansion. Application of the uncoupling agent reverses block to bidirectional conduction during partial cell‐to‐cell uncoupling (D), and block is obviously observed again after total uncoupling (E). Washout of the uncoupling agent establishes conduction again transiently (F‐H), while unidirectional block is observed after completion of washout.

Reproduced with permission from reference 327
Figure 15. Figure 15.

Overall structure of Ca2+‐ATPase in the native sarcoplasmic reticulum membrane at 14 Å resolution. Three‐dimensional structure of Ca2+‐ATPase in the native sarcoplasmic reticulum membrane was determined by cryoelectron microscopy and helical image analysis . The cytoplasmic part has a complex structure resembling the head and neck of a bird. The transmembrane domain has three segments and a luminal domain.

Figure 16. Figure 16.

Chemical modification of Ca2+‐ATPase. In this structural model, based on the predictions of Green and MacLennan , the helices of the stalk and membrane are clustered to show a channel for translocation of Ca2+. Specific points of reference are shown in the extramembranous region, including Asp 351 (the phosphorylation site), Lys 492 (derivatized by TNP‐8N3‐AMP), Lys 515 (derivatized by FITC), Thr 532 and Thr 533 (derivatized by 8N3‐[3H]‐ADP), and Lys 684 (derivatized by ATP‐PLP).

Figure 17. Figure 17.

Site‐directed mutagenesis of the Ca2+‐ATPase molecule. In this structural model, based on the predictions of Green and MacLennan , the arrangements of the helices of the stalk and membrane are clustered to create a channel for translocation of Ca2+. The locations of mutated residues are circled and the wild‐type residues are identified by a single letter code. The six residues, in the transmembrane region, are related to Ca2+ binding. The ten residues, in the cytoplasmic globular region, are related to the ATP binding and phosphoenzyme formation.

Figure 18. Figure 18.

Secondary structural model of phospholamban monomer. In this structural diagram, based on predictions of domain structure and hydropathy plots , the two α‐helices with a 3.6 residues/turn, domain IA and domain II, are connected by domain IB, which is unstructural. Domain I is exposed at the cytoplasmic surface, whereas domain II is anchored in the sarcoplasmic reticulum membrane. The residues are identified by a single letter code. Ser 16 and Thr 17 are phosphorylated by cAMP‐dependent protein kinase and Ca2+/calmodulin‐dependent protein kinase, respectively.

Figure 19. Figure 19.

Comparison of amino acid sequences among P‐type ATPases in the cytoplasmic phospholamban‐interacting site of the Ca2+‐ATPase. The amino acid sequence around the phospholamban (PLN)‐interacting site of SERCA2, presented in the single letter code, is aligned with homologous regions in other P‐type ATPases. Each line represents a different ATPase sequence, which are, from top to bottom: rabbit slow‐twitch/cardiac muscle sarcoplasmic reticulum Ca2+‐ATPase (SERCA2), rabbit fast‐twitch muscle sarcoplasmic reticulum Ca2+‐ATPase (SERCA1), rat nonmuscle sarcoplasmic reticulum Ca2+‐ATPase (SERCA3), human plasma membrane Ca2+‐ATPase PMCA, sheep plasma membrane Na+/K+‐ATPase, torpedo plasma membrane Na+/K+ ATPase, Saccharomyces cerevisiae H+‐ATPase, Neurospora crassa H+‐ATPase, Escherichia coli K+‐ATPase, and Streptococcus faecalis K+‐ATPase. Filled arrow indicates the aspartic acid 351 which is phosphorylated by ATP. Two closed arrows indicate Lys 397 and Lys 400, which can be crosslinked to PLN . The thick bar indicates a region corresponding to the 125I‐labeled peptides that appear to interact with PLN . The open bar indicates a synthetic peptide that was used to prevent the interaction between PLN and Ca2+‐ATPase . The asterisk indicates the SERCA2 amino acid residues that were shown to interact functionally with PLN in studies using site‐directed mutagenesis .

Figure 20. Figure 20.

Phospholamban‐interacting site in the cytoplasmic domains of SERCA2. Ca2+‐dependence of Ca2+ uptake rates for SERCA 2 and SERCA3 (A) and chimeras between them (B and C) were measured with (•) or without (^) coexpressed phospholamban (PLN). The domain structure of the SERCA chimera shown in the left side of each graph is based on the structural predictions defined in Figure . The open bars indicate SERCA2 sequence and the closed bars indicate SERCA3 sequence. B: Chimeric Ca2+‐ATPases between SERCA2 and SERCA3 were constructed as follows: CH1: the phosphorylation domain is from SERCA3 and the remainder is from SERCA2; CH2: the phosphorylation domain is from SERCA2 and the remainder is from SERCA3; CH3: the phosphorylation and the nucleotide‐binding/hinge domains are from SERCA2 and the remainder is from SERCA3; and CH4: the phosphorylation and the nucleotide‐binding/hinge domains are from SERCA3 and the remainder is from SERCA2. CH3 showed functional interaction with PLN. C: Individual amino acid residues in the SERCA3 sequence in CH1 were replaced by the corresponding residues in SERCA2. Mutant CH1‐M, in which 6 sequential amino acid residues Lys‐Asp‐Asp‐Lys‐Pro‐Val 402 from SERCA2 were introduced into the corresponding SERCA3 sequence, restored functional interaction with PLN. Note that nomenclature of chimera and mutant constructs are modified from those originally described by Toyofuku et al. .

Figure 21. Figure 21.

A model for the PKA‐regulation of the phospholamban‐SERCA2 system. The interaction between phospholamban (PLN) and the Ca2+‐ATPase is proposed to take place in the cytoplasmic and transmembrane parts of the two proteins. Unphosphorylated PLN suppresses Ca2+‐ATPase activity by associating charged residues in domain IA with the six serial amino acid residues Lys‐Asp‐Asp‐Lys‐Pro‐Val 402 in the cytoplasmic region of the Ca2+‐ATPase, and by forming an association between transmembrane sequences in both molecules. Phosphorylation of Ser16 in domain IA of PLN induces a conformational change resulting in dissociation of PLN from the Ca2+‐ATPase in both the cytoplasmic sequence and the transmembrane sequence.



Figure 1.

Schematic model of the ultrastructure of the cardiac cell. Contractile proteins are arranged in a regular array of thick and thin filaments. The A‐band represents the region of the sarcomere occupied by the thick filaments. Thin filaments extend variable distances into the A‐band, from either side. The I‐band represents the region of the sarcomere occupied excessively by thin filaments, which extend toward the center of the sarcomere from the Z‐lines. The sarcomere, the functional unit of the contractile apparatus, is defined as the region between a pair of Z‐lines, and contains two half I‐bands and one A‐band. The sarcoplasmic reticulum consists of the longitudinal reticulum and the terminal cisternae, which abut the transverse tubular system (T‐tubule). The T‐tubule is a sarcolemmal invagination, so that the lumen of the T‐tubules is continuous with the extracellular space. Slow Ca2+ channels in the T‐tubule are believed to be associated with the Ca2+ release channel in the junctional face of the terminal cisternae. In the lumen of the terminal cisternae, Ca2+‐binding proteins, calsequestrin, calreticulin, and histidine‐rich Ca2+ binding protein also exist. In the longitudinal reticulum, Ca2+‐ATPase and phospholamban exist in the membrane, and glycoproteins of 53 kDa and 160 kDa are located in the lumen.



Figure 2.

The reaction cycle. Steps involved in the process of ATP hydrolysis and Ca2+ transport by the sarcoplasmic reticulum Ca2+ ATPase. See text for details.



Figure 3.

Secondary structural model of the Ca2+‐ATPase molecule. This structural diagram is based on predictions of domain structure and a hydropathy plot . The bulk of the protein consists of a cytoplasmic globular headpiece structure and ten membrane‐spanning segments (M1–M10), which are connected via a stalk‐like cluster of α‐helices. The large globular cytoplasmic part is composed of three domains: the β‐strand domain, between segments M2 and M3; the phosphorylation domain, attached to segment M4 at one end and to the nucleotide‐binding domain at the other. The nucleotide binding domain runs into a hinge domain, which is attached to segment M5. The folding of the cytoplasmic structure is indicated schematically in accordance with the general principles established for antiparallel or parallel β‐sheet domains . The α‐helical sequence and the β‐sheet sequences are shown by cylinders and arrows, respectively. The numbers at the top and bottom of each transmembrane helix indicate the amino acid positions at each end of these helices.



Figure 4.

False‐color stereo shaded solid rendering of a section of a three‐dimensional reconstruction of the Z‐band from unstimulated rat soleus muscle. This 14 nm‐thick longitudinal section shows the interdigitating axial filaments and the cross‐connecting Z‐filament array. Axial filaments enter the Z‐band from the top (yellow) and bottom (orange) of the figure. The filaments are joined together by cross‐connecting Z‐filaments (blue), which also connect to the filamentous relaxed interconnecting body or Z‐RIB (red). In the I‐band near the top and bottom of the figure, some connections run directly between the axial filaments (magenta). Amorphous material (gray) obscures the filaments near the bottom corners of this section; scale bar = 10 nm).

Reprinted by permission of Rockefeller University Press


Figure 5.

Enzymatically dissociated left ventricular myocytes from adult dog (A) and rat (B). Bisbenzimide staining. A and B: bars = 100 μm.



Figure 6.

Photomicrographs showing mitotic figures detected in the ventricular myocardium of the human (A, B, D, E, and F) and rat (C) heart. The light microscopic mitotic images in panels A and B were found in a patient who died as a result of an extensive acute myocardial infarction. C illustrates by light microscopy a mitotic figure in a severely anemic adult rat with ventricular dysfunction. The mitotic images shown by confocal microscopy in D‐F were detected in a patient affected by end‐stage dilated cardiomyopathy. Large field area, illustrating by propidium iodide labeling only (green fluorescence; D) and by a combination of propidium iodide and α‐sarcomeric actin antibody staining of the myocyte cytoplasm (red fluorescence; E), a myocyte nucleus in metaphase (arrowhead) and a myocyte at completion of cytokinesis (arrow). Myocyte cytokinesis is shown at higher magnification in F. A, B, and D‐F: Paraffin‐embedded sections stained by hematoxylin and eosin (A and B) and propidium iodide (D‐F) and α‐sarcomeric actin (E and F). C: Semithin section of plastic‐embedded tissue stained by toluidine blue. A‐F: bars correspond to 10 μm.

D‐F: reproduced from ; copyright © 1998 National Academy of Sciences, USA


Figure 7.

Frozen sections of ventricular myocardium showing bromodeoxyuridine (BrdU) labeling of a myocyte nucleus after coronary artery narrowing. (A) BrdU labeling by immunofluorescence; (B): the same field shown by phase‐contrast microscopy and bisbenzimide H33258 fluorescence. A and B: bars = 10 μm.



Figure 8.

Semithin sections of plastic‐embedded rat ventricular myocardium after coronary artery narrowing (A) and coronary artery occlusion (B) showing mitotic figures. A: Methylene blue and safranin staining; B: Toluidine blue staining. A and B: bars = 10 μm.



Figure 9.

Peptide sequence alignment of mouse and human cardiac connexins. The color bar code at the top of the alignment indicates the degree of homology among all cardiac connexins, where red indicates identity, dark blue very low homology, and intermediate colors moderate similarity. (Alignment provided by Ms. M. Urban, using Clustal method with PAM 100 residue weight table, Lasergene program, DNASTAR Inc.) Regions corresponding to membrane‐spanning domains M1, M2, M3, M4 in Figure B are indicated.



Figure 10.

Propagation of slow intercellular calcium waves between wild‐type (A) and Cx43‐null (B) neonatal mouse cardiac myocytes loaded with an intracellular calcium indicator (Indo‐1AM) and imaged with real‐time confocal microscopy (Nikon RCM 8000). The mechanical stimulation of a single myocyte in culture (cell A, red arrow, uper left frames) initiates the propagation of the calcium wave captured in the pseudocolored display at 5 sec intervals (green: low Ca2+; red: high Ca2+). Graphical representations of the phenomenon as a function of time are shown to the right of the photographs; arrows indicate the moment of the stimulation. Note that the absence of Cx43 expression does not prevent the communication of the calcium signal, but reduces the efficacy of calcium wave spread, which extends to fewer cells per field than in wild‐type myocytes.



Figure 11.

Regulated expression of diphtheria toxin A in the hearts of transgenic mice results in spontaneous and inducible arrhythmias in vivo and in isolated‐perfused hearts. (A). Rhythm strip from awake, freely mobile transgenic mouse using a telemetric system shows a run of ventricular tachycardia. (B). Rapid ventricular tachycardia induced in an isolated‐perfused heart from a similar transgenic mouse. (C). Optical mapping showing normal activation profile (left panel) and perturbed epicardial activation (right panel) in a myopathic, transgenic heart.

From Lee et al. (1998)


Figure 12.

Effects of phospholamban mutations on apparent Ca2+ affinity of SERCA2 and location of residues in phospholamban that affect interaction with SERCA2 in cytoplasmic and transmembrane domains. Top: Ca2+‐dependence of Ca2+ uptake rates for SERCA2 were measured in the presence of coexpressed phospholamban (PLN) (solid line), and in the absence of phospholamban (dashed line). Ca2+‐dependence of Ca2+ uptake for SERCA2 coexpressed with wild‐type and mutant PLN is classified into three types in accordance with the extent of inhibitory actions on Ca2+ uptake rate. Wild‐type and no change phospholamban mutants lower the Ca2+ affinity for SERCA2 by about 0.34 pCa units (open circles), loss of function mutants do not alter the Ca2+ affinity for SERCA2 (red circles), and gain of function mutants diminish apparent Ca2+ affinity by up to 1 pCa unit, enhancing the inhibitory effect on Ca2+ uptake at low Ca2+ concentrations (green circles). Bottom: Location of phospholamban mutations that affect apparent Ca2+ affinity for SERCA2, presented in an α‐helical wheel configuration for both domain Ia and domain II. Each amino acid is classified into three types in accordance with the loss (red circles), gain (green circles), or no change (open circles) on inhibitory function. Phospholamban is abbreviated as PLN.



Figure 13.

Excitation of the isolated human heart. Isochrone map of the ventricular activation of an isolated human heart, based on measurements at 870 intramural electrode terminals. The horizontal planes into which the multi‐electrodes were inserted, and into which the heart was sectioned, are depicted. Each color represents a 5‐msec interval. Zero time is the beginning of the left ventricular cavity potential. White areas indicate either fatty tissue or parts of the myocardium for which no data are available. RA = right atrial cavity; LA = left atrial cavity; Ao = aorta; LV = left ventricular cavity; RV = right ventricular cavity; MV = mitral valve.

Reproduced with permission from reference


Figure 14.

Reversal of unidirectional block to bidirectional conduction by partial cell‐to‐cell uncoupling. Unidirectional block in patterned cell cultures (A) is produced by current‐to‐load mismatch at a geometrical expansion—i.e., an insertion of a small cell strand into a large tissue mass. The degree of electrical cell‐to‐cell coupling in the large area can be changed by application of a blocking agent (palmitoleic acid, 10 μmol/liter) through local superfusion (yellow area in B). During control (C) excitation (red) after stimulation of the strand is observed only in the small strand, while the unidirectional block leaves the large area at rest (blue), because of current‐to‐load mismatch at the expansion. Application of the uncoupling agent reverses block to bidirectional conduction during partial cell‐to‐cell uncoupling (D), and block is obviously observed again after total uncoupling (E). Washout of the uncoupling agent establishes conduction again transiently (F‐H), while unidirectional block is observed after completion of washout.

Reproduced with permission from reference 327


Figure 15.

Overall structure of Ca2+‐ATPase in the native sarcoplasmic reticulum membrane at 14 Å resolution. Three‐dimensional structure of Ca2+‐ATPase in the native sarcoplasmic reticulum membrane was determined by cryoelectron microscopy and helical image analysis . The cytoplasmic part has a complex structure resembling the head and neck of a bird. The transmembrane domain has three segments and a luminal domain.



Figure 16.

Chemical modification of Ca2+‐ATPase. In this structural model, based on the predictions of Green and MacLennan , the helices of the stalk and membrane are clustered to show a channel for translocation of Ca2+. Specific points of reference are shown in the extramembranous region, including Asp 351 (the phosphorylation site), Lys 492 (derivatized by TNP‐8N3‐AMP), Lys 515 (derivatized by FITC), Thr 532 and Thr 533 (derivatized by 8N3‐[3H]‐ADP), and Lys 684 (derivatized by ATP‐PLP).



Figure 17.

Site‐directed mutagenesis of the Ca2+‐ATPase molecule. In this structural model, based on the predictions of Green and MacLennan , the arrangements of the helices of the stalk and membrane are clustered to create a channel for translocation of Ca2+. The locations of mutated residues are circled and the wild‐type residues are identified by a single letter code. The six residues, in the transmembrane region, are related to Ca2+ binding. The ten residues, in the cytoplasmic globular region, are related to the ATP binding and phosphoenzyme formation.



Figure 18.

Secondary structural model of phospholamban monomer. In this structural diagram, based on predictions of domain structure and hydropathy plots , the two α‐helices with a 3.6 residues/turn, domain IA and domain II, are connected by domain IB, which is unstructural. Domain I is exposed at the cytoplasmic surface, whereas domain II is anchored in the sarcoplasmic reticulum membrane. The residues are identified by a single letter code. Ser 16 and Thr 17 are phosphorylated by cAMP‐dependent protein kinase and Ca2+/calmodulin‐dependent protein kinase, respectively.



Figure 19.

Comparison of amino acid sequences among P‐type ATPases in the cytoplasmic phospholamban‐interacting site of the Ca2+‐ATPase. The amino acid sequence around the phospholamban (PLN)‐interacting site of SERCA2, presented in the single letter code, is aligned with homologous regions in other P‐type ATPases. Each line represents a different ATPase sequence, which are, from top to bottom: rabbit slow‐twitch/cardiac muscle sarcoplasmic reticulum Ca2+‐ATPase (SERCA2), rabbit fast‐twitch muscle sarcoplasmic reticulum Ca2+‐ATPase (SERCA1), rat nonmuscle sarcoplasmic reticulum Ca2+‐ATPase (SERCA3), human plasma membrane Ca2+‐ATPase PMCA, sheep plasma membrane Na+/K+‐ATPase, torpedo plasma membrane Na+/K+ ATPase, Saccharomyces cerevisiae H+‐ATPase, Neurospora crassa H+‐ATPase, Escherichia coli K+‐ATPase, and Streptococcus faecalis K+‐ATPase. Filled arrow indicates the aspartic acid 351 which is phosphorylated by ATP. Two closed arrows indicate Lys 397 and Lys 400, which can be crosslinked to PLN . The thick bar indicates a region corresponding to the 125I‐labeled peptides that appear to interact with PLN . The open bar indicates a synthetic peptide that was used to prevent the interaction between PLN and Ca2+‐ATPase . The asterisk indicates the SERCA2 amino acid residues that were shown to interact functionally with PLN in studies using site‐directed mutagenesis .



Figure 20.

Phospholamban‐interacting site in the cytoplasmic domains of SERCA2. Ca2+‐dependence of Ca2+ uptake rates for SERCA 2 and SERCA3 (A) and chimeras between them (B and C) were measured with (•) or without (^) coexpressed phospholamban (PLN). The domain structure of the SERCA chimera shown in the left side of each graph is based on the structural predictions defined in Figure . The open bars indicate SERCA2 sequence and the closed bars indicate SERCA3 sequence. B: Chimeric Ca2+‐ATPases between SERCA2 and SERCA3 were constructed as follows: CH1: the phosphorylation domain is from SERCA3 and the remainder is from SERCA2; CH2: the phosphorylation domain is from SERCA2 and the remainder is from SERCA3; CH3: the phosphorylation and the nucleotide‐binding/hinge domains are from SERCA2 and the remainder is from SERCA3; and CH4: the phosphorylation and the nucleotide‐binding/hinge domains are from SERCA3 and the remainder is from SERCA2. CH3 showed functional interaction with PLN. C: Individual amino acid residues in the SERCA3 sequence in CH1 were replaced by the corresponding residues in SERCA2. Mutant CH1‐M, in which 6 sequential amino acid residues Lys‐Asp‐Asp‐Lys‐Pro‐Val 402 from SERCA2 were introduced into the corresponding SERCA3 sequence, restored functional interaction with PLN. Note that nomenclature of chimera and mutant constructs are modified from those originally described by Toyofuku et al. .



Figure 21.

A model for the PKA‐regulation of the phospholamban‐SERCA2 system. The interaction between phospholamban (PLN) and the Ca2+‐ATPase is proposed to take place in the cytoplasmic and transmembrane parts of the two proteins. Unphosphorylated PLN suppresses Ca2+‐ATPase activity by associating charged residues in domain IA with the six serial amino acid residues Lys‐Asp‐Asp‐Lys‐Pro‐Val 402 in the cytoplasmic region of the Ca2+‐ATPase, and by forming an association between transmembrane sequences in both molecules. Phosphorylation of Ser16 in domain IA of PLN induces a conformational change resulting in dissociation of PLN from the Ca2+‐ATPase in both the cytoplasmic sequence and the transmembrane sequence.

References
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Michihiko Tada, Toshihiko Toyofuku. Cardiac Sarcoplasmic Reticulum Ca2+‐ATPase. Compr Physiol 2011, Supplement 6: Handbook of Physiology, The Cardiovascular System, The Heart: 301-334. First published in print 2002. doi: 10.1002/cphy.cp020108