Molecular Regulation of the Na<sup>+</sup>‐Ca<sup>2+</sup> Exchanger

Philipson, K. D.; Nicoll, Debora A.; Matsuoka, Satoshi; Hryshko, Larry V.; Levitsky, Dmitrii I.; Weiss, James N.

doi:10.1111/j.1749-6632.1996.tb44766.x

Cited by 44 publications

(28 citation statements)

References 12 publications

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“…2+ exchanger molecule has 9 transmembrane segments (21, 22) with a large intracellular loop, which contains various regulatory sites (23,24). 'De-regulation' of the exchanger by cytosolic trypsin or a-chymotrypsin treatment has been demonstrated with respect to activation by intracellular Ca 2+ and ATP, Na + -dependent inactivation (25,26), inhibition by H + (27) and by the calmodulin inhibitor W-7 (28).…”

Section: Discussionmentioning

confidence: 99%

Blocking Effect of Bepridil on Na+/Ca2+ Exchange Current in Guinea Pig Cardiac Ventricular Myocytes

Watanabe

Kimura

2001

Japanese Journal of Pharmacology

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ABSTRACT-We examined the effect of bepridil, a class IV antiarrhythmic drug, on Na + /Ca 2+ exchange current (INCX) in single guinea pig cardiac ventricular cells using the whole-cell voltage clamp technique. INCX was recorded by ramp pulses from the holding potential of -60 mV in the presence of 140 mM Na + and 1 mM Ca 2+ in the external solution and 20 mM Na + and 119 nM free Ca 2+ (7 mM Ca 2+ and 20 mM BAPTA) in the internal solution. Bepridil suppressed INCX in a concentration-dependent manner. The IC50 value was 8.1 mM with a Hill coefficient of 0.8. Intracellular treatment with trypsin via the pipette solution attenuated the blocking effect of bepridil, suggesting that the inhibitory site is on the cytosolic side of the Naexchanger. In the absence of albumin in the external solution, 10 mM bepridil inhibited INCX by 46 ± 7% (n = 8), while bepridil blocked it by 28 ± 8% (n = 6) in the presence of albumin. Bepridil inhibited INCX in a supra-therapeutic concentration range.

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Section: Discussionmentioning

confidence: 99%

Blocking Effect of Bepridil on Na+/Ca2+ Exchange Current in Guinea Pig Cardiac Ventricular Myocytes

Watanabe

Kimura

2001

Japanese Journal of Pharmacology

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“…Molecular studies of the Na/Ca exchanger have revealed that NCX1 is the predominant Na/Ca exchanger gene and is expressed in almost every tissue but at a particularly high level in heart, brain, and kidney (2). Studies on the organization of the human NCX1 gene have revealed that it comprises at least 14 exons spread out over more than 200 kb of genomic DNA (3,4).…”

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confidence: 99%

A Circularized Sodium-Calcium Exchanger Exon 2 Transcript

Li¹,

Lytton

1999

Journal of Biological Chemistry

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Previous reports of Na/Ca exchanger gene 1 (NCX1) expression have revealed a major RNA transcript of 7 kilobase pairs (kb), minor transcripts of ϳ13 and ϳ4 kb, and a relatively abundant 1.8-kb RNA band. In the present report we demonstrate that the 1.8-kb message, which has a tissue and subcellular distribution matching that of full-length NCX1 but is not polyadenylated, corresponds to a perfectly circularized exon 2 species. The circular transcript contained the normal NCX1 start codon, a new stop codon introduced as a consequence of circularization, and encoded a protein corresponding to the NH 2 -terminal portion of NCX1, terminating just after amino acid 600 in the cytoplasmic loop. A linear version of the circular transcript was prepared and transfected into HEK-293 cells. A protein, matching the predicted size of ϳ70 kDa, was expressed, and the transfected cells possessed Na/Ca exchange activity. Although in native tissue we could not detect a protein corresponding exactly to that predicted from the circular transcript, a prominent band of slightly shorter size, possibly representing further proteolytic processing of circular transcript protein, was observed in membranes from LLC-MK2 cells and rat kidney.

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“…The expression of NCX2 and NCX3 seems to be restricted to the brain and skeletal muscle. The nonmammalian Na+-Ca 2+ exchanger isoforms have also been cloned (33,34). The mitochondrial Na+-Ca 2+ exchanger still remains to be cloned.…”

Section: Introductionmentioning

confidence: 99%

Na+-Ca2+ Exchanger: Physiology and Pharmacology.

1997

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ABSTRACT-TheNa+ -Ca2+ exchanger in the plasma membrane is a bidirectional electrogenic ion trans porter that couples the translocation of Na+ in one direction with that of Ca2+ in the opposite direction. This system is involved in regulation of intracellular Ca2+ concentration via the forward mode (Ca2+ extrusion) or the reverse mode (Ca2+ influx). There are two types of the plasma membrane Na+ -Ca2+ exchanger in an animal, and they are called the cardiac type and rod outer segment type. In addition, there is an electroneutral Na+ -Ca2+ exchanger present in mitochondria. Recent studies by the molecular biology technique show that there are at least 8 isoforms of the cardiac type (NCX1), and there are two other exchangers in the brain (NCX2 and NCX3). Due to new techniques of molecular biology and electro physiology, much evidence is accumulating with respect to the structure, mechanism, regulation, and physiological and pathological roles of the Na+ -Ca2+ exchanger. This review summarizes recent progress in this research field that is of nharmacolorical interest.

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Molecular Regulation of the Na⁺‐Ca²⁺ Exchanger

Cited by 44 publications

References 12 publications

Blocking Effect of Bepridil on Na+/Ca2+ Exchange Current in Guinea Pig Cardiac Ventricular Myocytes

Blocking Effect of Bepridil on Na+/Ca2+ Exchange Current in Guinea Pig Cardiac Ventricular Myocytes

A Circularized Sodium-Calcium Exchanger Exon 2 Transcript

Na+-Ca2+ Exchanger: Physiology and Pharmacology.

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Molecular Regulation of the Na+‐Ca2+ Exchanger

Cited by 44 publications

References 12 publications

Blocking Effect of Bepridil on Na+/Ca2+ Exchange Current in Guinea Pig Cardiac Ventricular Myocytes

Blocking Effect of Bepridil on Na+/Ca2+ Exchange Current in Guinea Pig Cardiac Ventricular Myocytes

A Circularized Sodium-Calcium Exchanger Exon 2 Transcript

Na+-Ca2+ Exchanger: Physiology and Pharmacology.

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Molecular Regulation of the Na⁺‐Ca²⁺ Exchanger