Brain Distribution of the Na⁺/Ca²⁺ Exchanger‐Encoding Genes NCX1, NCX2, and NCX3 and Their Related Proteins in the Central Nervous System

Abstract

In the central nervous system, the Na+/Ca2+ exchanger plays a fundamental role in controlling changes in the intracellular concentrations of Na+ and Ca2+ ions that occur in physiologic conditions such as neurotransmitter release, cell migration and differentiation, gene expression, as well as neuro‐degenerative processes. Three genes, NCX1, NCX2, and NCX3, encoding for Na+/Ca2+ exchanger isoforms have been cloned. In this review, by using non‐radioactive in situ hybridization and light immunohistochemistry with NCX isoform‐specific riboprobes and antibodies, respectively, a systematic brain mapping for both transcripts and proteins encoded by all three NCX genes is described. Intense expression of NCX transcripts and proteins was detected in the cerebral cortex, hippocampus, thalamus, metathalamus, hypothalamus, brainstem, spinal cord, and cerebellum. In these areas, NCX transcripts and proteins were often found with an overlapping distribution pattern, although specific brain areas displaying a peculiar expression of each exchanger isoform were also found. Furthermore, immunoelectron and confocal microscopy revealed the expression of the NCX1 isoform of the exchanger at both pre‐ and postsynaptic sites as well as in association with membranes of the endoplasmic reticulum. Collectively, these data suggest that the different isoforms of the Na+/Ca2+ exchanger appear to be selectively expressed in several CNS regions where they might underlie different functional roles.

Nonlinear [Ca2+] Signaling in Dendrites and Spines Caused by Activity-Dependent Depression of Ca2+Extrusion

“…NCX2 labeling is found in apical dendrites and spines of CA1 pyramidal neurons (Burette and Weinberg, personal communication), a finding consistent with studies of NCX2 knock-out mice, which exhibit slowing of Ca 2ϩ extrusion in the somato-dendritic compartment (Jeon et al, 2003). Other immunolocalization data suggest that NCX3 can also be found in CA1 dendrites (Canitano et al, 2002;Papa et al, 2003). NCKX can contribute to Ca 2ϩ extrusion in the somata of CA1 neurons (Kiedrowski, 2004), but little is known about the subcellular distributions of NCKX.…”

Two Sodium/Calcium Exchanger Gene Products, NCX1 and NCX3, Play a Major Role in the Development of Permanent Focal Cerebral Ischemia

“…5 These 3 proteins are differentially expressed in distinct regions of the central nervous system where they might underlie different physiological and pathophysiological functions. [6][7][8] Depending on the intracellular concentrations of Ca 2+ , [Ca 2+ ] i , and Na + , [Na + ] i , NCX can operate either in the forward mode, coupling the uphill extrusion of Ca 2+ to the influx of Na + ions, or in the reverse mode, mediating the extrusion of Na + and the influx of the Ca 2+ ions. 1 During ischemia, a compromission of the 2 plasma membrane ATP-dependent pumps, Na + /K + ATPase and Ca 2+ ATPase, occurs 9 with a consequent derangement of [Na + ] i and [Ca 2+ ] i .…”

Alteration in NCX-3 immunoreactivity within the gerbil hippocampus following spontaneous seizures

“…Moreover, persistent alterations in calcium balance in patients with epilepsy and in animal models of temporal lobe epilepsy (TLE) have been described in voltage-activated calcium currents, glutamate-mediated calcium influx, and the expression of calcium-binding proteins (9)(10)(11)(12). Previous studies also indicate that seizure-induced changes are accompanied by changes in the expression and/or function of calcium-extrusion proteins (13,14).…”

“…Briefly, NCX-3 immunoreactivity is abundantly expressed in the mossy fibers projecting from the granule cells located in the dentate gyrus in the rat hippocampus (13,14). In contrast, the expression of NCX-3 in the gerbil hippocampus was mainly observed in the CA2 pyramidal cells.…”