Cloning of Cardiac, Kidney, and Brain Promoters of the Feline ncx1 Gene

Barnes, Kimberly V.; Cheng, Guangmao; Dawson, Myra; Menick, Donald R.

doi:10.1074/jbc.272.17.11510

Cited by 49 publications

(50 citation statements)

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“…Although the large intracellular loop is not strictly necessary for the activity of the exchanger, it contains important regulatory elements (17)(18)(19). Its C-terminal portion is subjected to alternative splicing (20), which also occurs at the 5Ј-untranslated region of the gene (21)(22)(23). Numerous splicing variants have been described for NCX1.…”

mentioning

confidence: 99%

Calcineurin Controls the Transcription of Na+/Ca2+ Exchanger Isoforms in Developing Cerebellar Neurons

Guerini

Carafoli

2000

Journal of Biological Chemistry

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The Na ؉ /Ca 2؉ exchanger (NCX) and the plasma membrane Ca 2؉ -ATPase export Ca 2؉ from the cytosol to the extracellular space. Three NCX genes (NCX1, NCX2, and NCX3), encoding proteins with very similar properties, are expressed at different levels in tissues. Essentially, no information is available on the mechanisms that regulate their expression. Specific antibodies have been prepared and used to explore the expression of NCX1 and NCX2 in rat cerebellum. The expression of NCX2 became strongly up-regulated during development, whereas comparatively minor effects were seen for NCX1. This was also observed in cultured granule cells induced to mature in physiological concentrations of potassium. By contrast, higher K ؉ concentrations, which induce partial depolarization of the plasma membrane and promote the influx of Ca 2؉ , caused the complete disappearance of NCX2. Reverse transcription-polymerase chain reaction analysis showed that the process occurred at the transcriptional level and depended on the activation of the Ca 2؉ calmodulin-dependent protein phosphatase, calcineurin. The NCX1 and NCX3 genes were also affected by the depolarizing treatment: the transcription of the latter became upregulated, and the pattern of expression of the splice variants of the former changed. The effects on the NCX1 and NCX3 genes were calcineurin-independent.Hormonal and electrical stimuli promote the penetration of Ca 2ϩ into cells to activate cellular responses. Ca 2ϩ must then be continuously extruded, because its uncontrolled increase in the cytosol would lead to cell death. Two systems, a pump (1) and a Na ϩ /Ca 2ϩ exchanger (2), eject Ca 2ϩ . The latter system, which is particularly active in heart and neurons, uses the Na ϩ gradient generated by the Na ϩ /K ϩ -ATPase to remove Ca 2ϩ from the cytosol; under normal conditions 3 Na ϩ ions are exchanged for 1 Ca 2ϩ . The cDNA of exchanger type 1 (NCX1) 1 has been cloned from mammalian (3-8), amphibian (9), and invertebrate (10, 11) tissues. A comparison of the sequences shows a high level of conservation. The mature NCX1 is a glycosylated protein (12) of 970 amino acids, the first 32 of which are post-translationally cleaved off (13-15). The original membrane topography model based on hydropathy analysis predicted 11 transmembrane domains, separated by small loops and by a large intracellular loop (Ͼ500 amino acids) between transmembrane domains 5 and 6. A more recent model based on cysteine accessibility studies has revised the number of predicted transmembrane domains down to 9 (16), eliminating 2 from the C-terminal half of the exchanger. Although the large intracellular loop is not strictly necessary for the activity of the exchanger, it contains important regulatory elements (17-19). Its C-terminal portion is subjected to alternative splicing (20), which also occurs at the 5Ј-untranslated region of the gene (21-23). Numerous splicing variants have been described for NCX1. The amount of the major variant present in neurons (the AD isoform) is altered by protein kinase...

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confidence: 99%

Calcineurin Controls the Transcription of Na+/Ca2+ Exchanger Isoforms in Developing Cerebellar Neurons

Guerini

Carafoli

2000

Journal of Biological Chemistry

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“…Consequently, individual 5Ј-leaders and the presumed exons encoding them were called heart-, brain-, and kidneyspecific (8). The main difference between the model of the multipartite promoter presented here and those implied from earlier reports is that no single transcription start can be called "tissue-specific," although expression of exon 1c clearly dominates in kidney and exon 1d in heart (Fig.…”

Section: Physical Map and Tissue-specific Expression Of The Ncx1 Exonsmentioning

confidence: 56%

“…However, although the position of the clustered three putative first exons is very similar in rat and human genomic DNA ( Figs. 1 and 2), the pattern of their expression in different tissues (see below and also under "Discussion") does not seem to agree with the simple model recently presented in Barnes et al (8). Since the previously used terms "brain-," "heart-," and "kidney"-specific exons appear confusing, they were replaced by a neutral designation "exon 1a, 1b, 1c," and so forth.…”

Section: Identification Of Alternative First Exons In Rat Andmentioning

confidence: 91%

“…Although it was readily obvious from data accumulated in sequence data bases, a study in rat (7) first conclusively demonstrated that NCX1 transcripts in different tissues have at least three different 5Ј-untranslated leaders, which are spliced to a common core containing the protein coding sequence. A recent publication linked these leaders to three "heart," "kidney," and "brain" alternative promoters (8) in the cat NCX1 gene. While most eukaryotic genes are controlled by a complex array of cis-regulatory elements modulating transcriptional activity at a single site, a substantial number of genes have recently been found to utilize multiple promoters (9 -14).…”

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Cloning of the Multipartite Promoter of the Sodium-Calcium Exchanger Gene NCX1 and Characterization of Its Activity in Vascular Smooth Muscle Cells

Scheller¹,

Kraev²,

Skinner³

et al. 1998

Journal of Biological Chemistry

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The sodium-calcium exchange activity is mediated by proteins encoded in a small gene family, of which the gene NCX1 is ubiquitously expressed in mammalian tissues. In this study, the multipartite promoter of this gene was analyzed in the human and rat genomes by means of DNA cloning, reverse transcriptase-polymerase chain reaction, and transient transfection of fusion constructs with the firefly luciferase gene into cultured rat aortic smooth muscle cells. The gene-proximal promoter, located 30 kilobase pairs (kb) away from the first coding exon 2, has features of a GC-rich housekeeping promoter and is apparently always active; in specific tissues, however, it is augmented by one or two additional promoters, located either within 1.5 kb upstream of it, or 35 kb upstream. The gene proximal promoter shows the highest activity in aortic smooth muscle cells. In mammalian species transcripts from all three promoters undergo splicing via an intermediate, containing two noncoding exons, of which the downstream one is normally not present in the terminal splicing product.

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“…The NCX1 gene is under the control of tissue-specific promoters that contain regulatory elements that respond to tissue-specific transcriptional regulation (3,40,41,53). In contrast, the promoter regions of the genes encoding NCKX proteins have not been analyzed in any detail for transcription factor binding sites or tissue-specific elements (31,60).…”

Section: Regulationmentioning

confidence: 99%

K⁺-Dependent Na⁺/Ca²⁺Exchangers: Key Contributors to Ca²⁺Signaling

Visser

Lytton

2007

Physiology

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Ca 2+ acts as a ubiquitous second messenger to control a wide variety of physiological processes by relaying information within mammalian cells (6). For example, Ca 2+ signals trigger fertilization, control development and differentiation, coordinate cellular functions, and even play roles in cell death. The large variety of functional effects are dictated by the spatial and temporal nature of the Ca 2+ signals and by the cellular context in which they occur, that is, the tissue and cell-specific complement of Ca 2+ influx/efflux pathways and downstream targets determine the final outcome. Cytosolic Ca 2+ influx typically occurs when Ca 2+ channels localized to the plasma or endoplasmic reticular membranes open in response to various stimuli such as membrane depolarization or ligand binding (5). Ca 2+ can be subsequently removed from the cytosol by various mechanisms: sarco/endoplasmic reticulum Ca 2+ ATPases (SERCA) and plasma membrane Ca 2+ ATPases (PMCA) utilize the energy from ATP hydrolysis to pump Ca 2+ into the endoplasmic reticulum or outside the cell, respectively, and Na + /Ca 2+ exchangers extrude cytosolic Ca 2+ in exchange for extracellular Na + . In certain cellular contexts, such as localized signals in the dendritic spines of neurons, Ca 2+ flux across the plasma membrane predominates over that from intracellular stores (2, 49). In such cases, PMCA proteins control the resting Ca 2+ concentrations because of their high-affinity/lowcapacity transport properties, whereas Na + /Ca 2+ exchangers display low-affinity/high-capacity transport properties that are ideally suited for cytosolic clearance when Ca 2+ is elevated following a signaling event. Detailed knowledge of the physiological and biochemical properties of calcium channels and transporters is critical to understanding the mechanisms of Ca 2+ signaling in various cellular contexts. This review will focus on recent progress in the understanding of the physiology, function, structure, and regulation of the recently identified family of K + -dependent Na + /Ca 2+ exchangers. K + -Dependent and Independent Na + /Ca 2+ ExchangersThere are two families of Na + /Ca 2+ exchangers in mammalian cells: those that are K + -dependent (NCKX) and those that are K + -independent (NCX). Physiologically, NCX proteins function by extruding cytosolic Ca 2+ in exchange for extracellular Na + ions, whereas NCKX proteins extrude cytosolic Ca 2+ and K + in exchange for Na + ions, which in both cases is referred to as forward mode exchange. In conditions of altered ion gradients and membrane potential, these exchangers can also mediate Ca 2+ entry or so-called reverse mode operation. Three NCX and five NCKX isoforms have been identified by molecular cloning. NCX1 is predominantly expressed in the heart, brain, and kidney, although it is also present in a broad variety of cell types, whereas NCX2 and 3 expression is limited to brain and skeletal muscle (38,42,43). NCKX1 is exclusively expressed in retinal rod outer segments, whereas NCKX2 is expressed in brain and c...

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Cloning of Cardiac, Kidney, and Brain Promoters of the Feline ncx1 Gene

Cited by 49 publications

References 55 publications

Calcineurin Controls the Transcription of Na+/Ca2+ Exchanger Isoforms in Developing Cerebellar Neurons

Calcineurin Controls the Transcription of Na+/Ca2+ Exchanger Isoforms in Developing Cerebellar Neurons

Cloning of the Multipartite Promoter of the Sodium-Calcium Exchanger Gene NCX1 and Characterization of Its Activity in Vascular Smooth Muscle Cells

K⁺-Dependent Na⁺/Ca²⁺Exchangers: Key Contributors to Ca²⁺Signaling

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Cloning of Cardiac, Kidney, and Brain Promoters of the Feline ncx1 Gene

Cited by 49 publications

References 55 publications

Calcineurin Controls the Transcription of Na+/Ca2+ Exchanger Isoforms in Developing Cerebellar Neurons

Calcineurin Controls the Transcription of Na+/Ca2+ Exchanger Isoforms in Developing Cerebellar Neurons

Cloning of the Multipartite Promoter of the Sodium-Calcium Exchanger Gene NCX1 and Characterization of Its Activity in Vascular Smooth Muscle Cells

K+-Dependent Na+/Ca2+Exchangers: Key Contributors to Ca2+Signaling

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K⁺-Dependent Na⁺/Ca²⁺Exchangers: Key Contributors to Ca²⁺Signaling