Functional effects of caloxin 1c2, a novel engineered selective inhibitor of plasma membrane Ca<sup>2+</sup>‐pump isoform 4, on coronary artery

Pande, Jyoti; Szewczyk, Magdalena M.; Kuszczak, Iwona; Grover, Shawn; Escher, Emanuel; Grover, Ashok K.

doi:10.1111/j.1582-4934.2008.00140.x

Cited by 25 publications

(29 citation statements)

References 64 publications

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“…This method was used for caloxin 1b1 [92]. The hypothesis was that altering one, two, or three residues in caloxin 1b1 may improve its affinity and isoform selectivity, and yet maintain its ability to inhibit PMCA.…”

Section: Screening Phage Display Librariesmentioning

confidence: 99%

Caloxins: a novel class of selective plasma membrane Ca2+ pump inhibitors obtained using biotechnology

Szewczyk

Pande

Grover

2007

Pflugers Arch - Eur J Physiol

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Plasma membrane Ca2+ pumps (PMCA) extrude cellular Ca2+ with a high affinity and hence play a major role in Ca2+ homeostasis and signaling. Caloxins (selective extracellular PMCA inhibitors) would aid in elucidating the physiology of PMCA. PMCA proteins have five extracellular domains (exdoms). Our hypotheses are: 1) peptides that bind selectively to each exdom can be invented by screening a random peptide library, and 2) a peptide can modulate PMCA activity by binding to one of the exdoms. The first caloxin 2a1, selected for binding exdom 2 was selective for PMCA (Ki=529 microM). It has been used to examine the physiological role of PMCA. PMCA isoforms are encoded by four genes. PMCA isoform expression differs in various cell types, with PMCA1 and 4 being the most widely distributed. There are differences between PMCA1-4 exdom 1 sequences, which may be exploited for inventing isoform selective caloxins. Using exdom 1 of PMCA4 as a target, modified screening procedures and mutagenesis led to the high-affinity caloxin 1c2 (Ki=2.3 microM for PMCA4). It is selective for PMCA4 over PMCA1, 2, or 3. We hope that caloxins can be used to discern the roles of individual PMCA isoforms in Ca2+ homeostasis and signaling. Caloxins may also become clinically useful in cardiovascular diseases, neurological disorders, retinopathy, cancer, and contraception.

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Section: Screening Phage Display Librariesmentioning

confidence: 99%

Caloxins: a novel class of selective plasma membrane Ca2+ pump inhibitors obtained using biotechnology

Szewczyk

Pande

Grover

2007

Pflugers Arch - Eur J Physiol

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“…In vascular smooth muscle, ATP2B1 and ATP2B4 have been also shown to be expressed. 18 However, there were few reports evaluating the role of ATP2B1 in VSMCs. Thus, we decided to knock out the ATP2B1 gene of VSMCs to clarify the function of the ATP2B1 gene in hypertension theoretically in humans.…”

Section: Implication Of Atp2b1 In Blood Pressure Control and Functionmentioning

confidence: 99%

Mice Lacking Hypertension Candidate Gene ATP2B1 in Vascular Smooth Muscle Cells Show Significant Blood Pressure Elevation

Kobayashi

Hirawa²,

Tabara³

et al. 2012

Hypertension

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Abstract-We reported previously that ATP2B1 was one of the genes for hypertension receptivity in a large-scale Japanese population, which has been replicated recently in Europeans and Koreans. ATP2B1 encodes the plasma membrane calcium ATPase isoform 1, which plays a critical role in intracellular calcium homeostasis. In addition, it is suggested that ATP2B1 plays a major role in vascular smooth muscle contraction. Because the ATP2B1 knockout (KO) mouse is embryo-lethal, we generated mice with vascular smooth muscle cell-specific KO of ATP2B1 using the Cre-loxP system to clarify the relationship between ATP2B1 and hypertension. The KO mice expressed significantly lower levels of ATP2B1 mRNA and protein in the aorta compared with control mice. KO mice showed significantly higher systolic blood pressure as measured by tail-cuff method and radiotelemetric method. Similar to ATP2B1, the expression of the Na 1 In the Millennium Genome Project 2 we identified single nucleotide polymorphisms located upstream or within the ATP2B1 gene as strong susceptible polymorphisms for hypertension in Japanese. Some of these findings have been replicated in individuals of European descent in the Global Blood Pressure Genetics sample and have also been validated in other studies in individuals of European descent, 3 Koreans, 4-6 and Japanese. 7 The single nucleotide polymorphisms of ATP2B1 identified in these studies showed a significant association with hypertension in various large-scale study populations with different methods, genome-wide association study in the Cohorts for Heart and Aging Research in Genomic Epidemiology Consortium and the Korean study and candidate gene analysis in our previous study. However, the functional roles of ATP2B1 in blood pressure control have not yet been proven in vivo. The ATP2B1-null mutant mouse has been reported to be embryolethal 8 ; thus, we need to make a conditional knockout (KO) mouse model of ATP2B1 using the Cre-loxP system to reveal the function of the gene. Because the ATP2B1 gene encodes one of the calcium pumps and plays an important role in contraction of bladder smooth muscle, 9 we selected vascular smooth

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“…In contrast to studies on transgenic mice it has been shown that the PMCA inhibitor caloxin 1c2, which has 10x greater affinity for PMCA4 when compared to PMCA1, 2 or 3, increased coronary artery smooth muscle contractility [86]. Studies in cultured vascular smooth muscle cells have shown that inhibition of PMCA4 with another PMCA4 inhibitor, caloxin 1b1, results in a rise in [Ca 2+ ] i .…”

Section: Pmca4 and Vascular Contractilitymentioning

confidence: 87%

Ca2+ signalling in cardiovascular disease: the role of the plasma membrane calcium pumps

Cartwright

Oceandy

Austin

et al. 2011

Sci. China Life Sci.

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The plasma membrane calcium ATPases (PMCA) are a family of genes which extrude Ca 2+ from the cell and are involved in the maintenance of intracellular free calcium levels and/or with Ca 2+ signalling, depending on the cell type. In the cardiovascular system, Ca 2+ is not only essential for contraction and relaxation but also has a vital role as a second messenger in signal transduction pathways. A complex array of mechanisms regulate intracellular free calcium levels in the heart and vasculature and a failure in these systems to maintain normal Ca 2+ homeostasis has been linked to both heart failure and hypertension. This article focuses on the functions of PMCA, in particular isoform 4 (PMCA4), in the heart and vasculature and the reported links between PMCAs and contractile function, cardiac hypertrophy, cardiac rhythm and sudden cardiac death, and blood pressure control and hypertension. It is becoming clear that this family of calcium extrusion pumps have essential roles in both cardiovascular health and disease.

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Functional effects of caloxin 1c2, a novel engineered selective inhibitor of plasma membrane Ca²⁺‐pump isoform 4, on coronary artery

Cited by 25 publications

References 64 publications

Caloxins: a novel class of selective plasma membrane Ca2+ pump inhibitors obtained using biotechnology

Caloxins: a novel class of selective plasma membrane Ca2+ pump inhibitors obtained using biotechnology

Mice Lacking Hypertension Candidate Gene ATP2B1 in Vascular Smooth Muscle Cells Show Significant Blood Pressure Elevation

Ca2+ signalling in cardiovascular disease: the role of the plasma membrane calcium pumps

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Functional effects of caloxin 1c2, a novel engineered selective inhibitor of plasma membrane Ca2+‐pump isoform 4, on coronary artery

Cited by 25 publications

References 64 publications

Caloxins: a novel class of selective plasma membrane Ca2+ pump inhibitors obtained using biotechnology

Caloxins: a novel class of selective plasma membrane Ca2+ pump inhibitors obtained using biotechnology

Mice Lacking Hypertension Candidate Gene ATP2B1 in Vascular Smooth Muscle Cells Show Significant Blood Pressure Elevation

Ca2+ signalling in cardiovascular disease: the role of the plasma membrane calcium pumps

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Functional effects of caloxin 1c2, a novel engineered selective inhibitor of plasma membrane Ca²⁺‐pump isoform 4, on coronary artery