October 5, 2001 -- The 4th International Conference on Sodium-Calcium Exchange: Cellular and Molecular Physiology of Sodium-Calcium Exchange, will convene October 10-14, 2001 in Banff, Alberta, Canada. This gathering of more than 100 international and interdisciplinary experts is being sponsored by the American Physiological Society (APS).
Background
The physiological functions of vision, secretion and cardiac contractility are strongly dependent on sodium-calcium (Na+-Ca2+) exchange activity, according to the proceedings of the last NCX conference held in 1995 and published by the New York Academy of Sciences (Volume 779, p. xiii). Research efforts stem from the realization that “In many cell types, sodium-calcium exchange is the primary mechanism of calcium extrusion, and small changes of sodium-calcium exchange activity have large effects on cell function. In heart and in brain, sodium-calcium exchange activity likely becomes pivotal in pathological settings with possible outcomes of calcium overload, altered electrical activity and ultimately cell death.” (p. xiii).
Since the Na+-Ca2+ exchanger (NCX) was first identified in heart muscle in 1968-1969 (p.7), it has been identified in virtually every tissue examined as well as in a variety of species, including human, dog, squid and fruit fly. The 1990 cloning of NCX1 from heart led to the discovery of different NCX isoforms in kidney, brain and vascular smooth muscle, as well as to the cloning of two new NCX genes, NCX2 and NCX3 from mammalian brain and skeletal muscle. A separate sub-family of Na+/Ca2+ exchangers, NCKX, was also identified in eye, brain and smooth muscle, that depend upon and transport potassium (K+) as well as Na+ and Ca2+. These data have provided further avenues for scientific exploration for the benefit of human health.
Conference and Featured Topics
This year’s conference focuses on Na+/Ca2+ exchange at the cellular and molecular level. The depth and breadth of the presentations is solid evidence of the advances that have been made since the last meeting, held in 1995 in Woods Hole, MA.
The following presentations are among the highlights of the invited presentations and poster sessions being conducted during the gathering:
A Potential New Approach to Cancer Gene Therapy
Ca2+ may trigger programmed cell death (apoptosis) and regulate death-specific enzymes. Therefore, the development of strategies to control Ca2+ homeostasis may represent a potential approach to prevent or enhance cell apoptosis. To test this hypothesis, Dr. André Herchuelz and colleagues at the Brussels University School of Medicine, Laboratory of Pharmacology, Brussels, Belgium, conducted an experiment in which the plasma membrane Na+/Ca2+ exchanger (NCX1.7 isoform) was stably overexpressed in insulin-secreting tumor cells. Based on the results, the researchers concluded that by increasing apoptosis and decreasing cell proliferation, overexpression of Na+/Ca2+ exchanger may represent a new potential approach in cancer gene therapy.
Sodium Calcium Exchangers in Olfactory Tissue
Olfactory marker protein (OMP) is a 19-kDa cytoplasmic protein selectively expressed in mature olfactory sensory neurons from fish to humans. OMP-null mice show delays in the onset and recovery phases of electro-olfactograms following odorant stimulation when compared to controls. As defective Ca2+ regulation could be responsible for these effects, Dr. Dan Schulze and his colleagues at the University of Maryland’s Department of Microbio-Immunology and Department of Anatomy/Neurobiology, examined the interaction of OMP and the Na+/Ca2+ exchanger in Xenopus oocytes and observed an OMP concentration-dependent decrease in Na+/Ca2+ exchanger activity. Their analyses, which Dr. Schulze will discuss in detail at the meeting, provide the first molecular demonstration of the presence of Na+/Ca2+ exchangers in olfactory tissue and their interaction with OMP.
The Brain and Functional Properties of the K+-Dependent Na+/Ca2+ Exchanger Isoforms
In the more than three decades since it was first characterized, researchers have come to appreciate that the Na+/Ca2+ exchanger molecule plays a critical role in Ca2+ homeostasis in neurons. Genome analysis indicates that Na+/Ca2+ exchangers are a superfamily encoded by seven different genes that are divided into two groups: the Na+/Ca2+ exchangers (NCX; SLC8) and the Na+/Ca2++K+ exchangers (NCKX; SLC24). The unique role that each exchanger gene plays in neuronal calcium homeostasis is being investigated by Dr. Jonathan Lytton and his colleagues at the Department of Biochemistry & Molecular Biology, University of Calgary, Calgary, Alberta, Canada. Dr. Lytton will present recent findings examining both the expression pattern and functional properties of the K+-dependent Na+/Ca2+ exchanger isoforms expressed in the brain.
Na+/Ca2+ Exchanger Overexpression Impairs Contractility
In the failing human heart, expression of sarcolemmal Na+/Ca2+ exchanger (NCX) is increased. Because NCX can work in the forward and reversed mode, increased expression could result in cellular calcium loss or gain. Correlative analysis in failing human hearts indicates that NCX predominantly eliminates calcium and contributes to reduced sarcoplasmic reticulum calcium load. To test the concept, Professors Gerd Hasenfuss and W. Schillinger, of the Department of Cardiology and Pneumology at the University of Goettingen, Goettingen, Germany, examined the effect of NCX overexpression in isolated myocytes. The results of their study show that overexpression of NCX causes depression of contractile function similar to that observed in failing human myocardium. This supports the hypothesis that upregulation of NCX can result in myocardial failure.
Cyclosporin A, Hypertrophy and Heart Failure
Female homozygous transgenic mice that overexpress NCX1 develop heart failure and premature death following the first and second pregnancy. Earlier research has demonstrated that treatment of cardiac hypertrophy in pressure-overloaded wild-type mice with cyclosporin A (CSA; a calcineurin inhibitor), can prevent cardiac hypertrophy and downregulation of NCX1 expression. To establish the significance of NCX1 upregulation in cardiac hypertrophy, Susanne B. Nicholas, MD, Ph.D., in the Department of Medicine at the University of California, Los Angeles, investigated the effect of CSA on NCX1 expression and development of cardiac hypertrophy in transverse aortic constriction-induced cardiac hypertrophy in NCX1-overexpressing mice. Dr. Nicholas will discuss her findings and expand upon her work on the regulation of Na/Ca exchanger expression in cardiac hypertrophy during her Saturday, October 13 presentation.
Cardiac NCX in Neonates vs. Adults
The neonatal heart is relatively more dependent on NCX for Ca2+ handling during contraction and relaxation than is the adult heart. Neonates are more sensitive to myocardial depression by volatile anesthetics such as halothane and sevoflurane. Using loaded rat cardiac myocytes, Y.S. Prakash, Ph.D., and his colleagues in the Department of Anesthesiology at the Mayo Clinic examined the theory that anesthetics produce greater myocardial depression in neonates via greater interference with NCX regulation by phosphorylation. The results of their work indicate qualitative and quantitative differences in NCX regulation of neonatal vs. adult heart, with less efficient signal transduction between b-adrenoceptor and cAMP pathway in neonates. Their data also support the hypothesis that volatile anesthetics produce greater myocardial depression in neonates via greater interference with NCX regulation.
The American Physiological Society (APS) is sponsoring this conference, the first of its two Fall conferences this year. The APS was founded in 1887 to foster basic and applied science, much of it relating to human health. The Bethesda, MD-based Society has more than 10,000 members and publishes 3,800 articles in its 14 peer-reviewed journals each year.