Encyclopedia of Signaling Molecules

2018 Edition
| Editors: Sangdun Choi

SLC24A Family (K+-Dependent Na+-Ca2+ Exchanger, NCKX)

  • Ali H. Jalloul
  • Robert T. Szerencsei
  • Tatiana P. Rogasevskaia
  • Paul P. M. Schnetkamp
Reference work entry
DOI: https://doi.org/10.1007/978-3-319-67199-4_101860

Synonyms

Historical Background

Tightly controlled changes in cytosolic free Ca2+ concentration are widely involved in cell signaling in most tissues of our body. Free Ca2+ concentration is increased through the activation of a wide range of surface or intracellular Ca2+ channels and is returned to resting values through the action of ATP-driven Ca2+ pumps located in the plasma membrane and endoplasmic reticulum as well as Na+/Ca2+ exchangers located on the plasma membrane. By the mid 1980s, it had been established that the surface membrane of the outer segments of retinal rod photoreceptors (ROS) contained a potent Na+-Ca2+ exchange mechanism (Schnetkamp 1980; Yau and Nakatani 1984), and, in 1988, the Na+-Ca2+ exchanger protein was purified from bovine ROS as a 220 kDa glycoprotein (Cook and Kaupp 1988). In 1989, it was discovered that Na+-Ca2+ exchange in ROS was a K+-dependent Na+/Ca2+ exchange process operating at a stoichiometry of four Na+ ions exchanged against one Ca2+ plus one K+ ion. This ion exchanger protein is now referred to as NCKX1 (Cervetto et al. 1989; Schnetkamp et al. 1989). In the early 1990s, the functional properties and physiological role of the NCKX1 exchanger in ROS were examined in significant detail as described below, and, to date, these remain the only detailed studies of NCKX function and physiology in native tissues. In 1992, the cDNA of the full-length bovine ROS NCKX was cloned and shown to encode a protein of 1,199 amino acids (Reiländer et al. 1992). In subsequent years, four additional and distinct human genes were identified encoding the NCKX2–5 proteins (Schnetkamp 2013). We now know that genes encoding NCKX proteins belong to the CaCA superfamily of cation/Ca2+ exchangers and their closest relatives in the superfamily are the Na+/Ca2+ exchanger (NCX) proteins carrying out K+-independent Na+/Ca2+ exchange and studied extensively in cardiomyocytes: the SLC24 gene family encodes the human NCKX1–5 proteins (Schnetkamp et al. 2014), while the SLC8 gene family encodes the human NCX1–3 proteins (Khananshvili 2013). NCKX1–5 proteins range between 500 and 750 residues with the exception of the mammalian NCKX1 proteins which can be as large as 1,200 residues. The increase in size is due to poorly conserved expansions of the two large hydrophilic loops that are present in all NCKX proteins (Szerencsei et al. 2002). NCKX and NCX proteins show very limited sequence homology restricted to two short segments of around 50 residues each. However, the topological arrangement of transmembrane α helices is now thought to be the same for both NCX and NCKX (Szerencsei et al. 2013). Initially, the SLC24 gene family was thought to contain a sixth member encoding NCKX6, but this is now designated as NCLX or Li+-permeable Na+-Ca2+ exchanger encoded by the SLC8B1 gene (Khananshvili 2013). In the next three sections, we will review the functional properties and physiological role of NCKX1 in phototransduction in ROS and then compare in situ functional properties with those obtained for NCKX1–4 proteins after heterologous expression in the human embryonic kidney cells (HEK293) cells. Next, we will discuss physiological roles for NCKX proteins as revealed by gene deletion studies and analysis of SLC24 mutations found in patients with congenital diseases, and, finally, we will review our current knowledge of structure-function relationships of NCKX as revealed by studies on wild-type (WT) NCKX2 and a large collection of mutant NCKX2 proteins expressed in cell lines.

Functional Properties and Physiological Roles

K+-dependent Na+/Ca2+ exchangers (NCKX) are bidirectional plasma membrane Ca2+ transporters that utilize the Na+ and K+ ionic gradients across the cell surface membrane and can remove Ca2+ from the cytoplasm or move Ca2+ into the cell, dependent on the prevailing Na+ and K+ gradients. NCKX proteins are thought to operate through the alternating access model of ion transport (Schnetkamp 2013, 2014), which is the accepted mode of transport for all primary and secondary transporters. This transport model implies that, within the transporter protein, the same binding pocket coordinates substrates when the transporter is in either the cytoplasmic configuration or the extracellular configuration. The alternating access model can be described with Michaelis-Menten kinetics, which defines an apparent substrate dissociation or Michaelis-Menten constant (Km) as a measure of substrate affinity. In the NCKX model, the cation-binding sites bind either Ca2+ and K+ or four Na+ ions, therefore suggesting that there exists a site for which Ca2+ and Na+ compete for binding and other sites where Na+ and K+ compete (Schnetkamp et al. 2014). However, transport only occurs with the occupancy of either one Ca2+ and one K+ or with the occupancy of four Na+ ions. Transport studies have shown that NCKX proteins are absolutely selective for Na+; however, Ca2+ and K+ ions can be replaced by Sr2+ and Rb+ (or NH4+), respectively. The ionic affinities of NCKX1–4 proteins have been recently reviewed (Schnetkamp et al. 2014; Jalloul et al. 2016b): the external Km for Ca2+ ions ranged between 1 and 5 μM, while the internal Km for Ca2+ has been shown to be 0.5–1 μM. The internal and external Km values for K+ range between 1 and 5 mM, while the internal and external Km values for Na+ range from 30 to 80 mM dependent on the presence of competing alkali cations. The transport stoichiometry has been determined to be four Na+ ions in exchange for one Ca2+ and one K+ ion for NCKX1 protein in situ (Cervetto et al. 1989; Schnetkamp et al. 1989) and NCKX2 proteins expressed in cell lines (Szerencsei et al. 2001).

Detailed in situ studies have been mostly limited to the role of NCKX1 in retinal rod photoreceptors summarized in Fig. 1. In the dark, the outer segments of retinal rod and cone photoreceptors show a sustained inward Na+ and Ca2+ current carried by the cGMP-gated channels (CNG) and cause a sustained depolarization of the plasma membrane. The channels are kept open in the dark by the presence of high concentrations of the excitatory messenger cGMP, which is maintained through the activity of a membrane bound and Ca2+-regulated guanylyl cyclase. As about 15–20% of the dark inward current is carried by Ca2+, the outer segment requires an active Ca2+ extrusion mechanism in the form of the NCKX1 protein to counter the Ca2+ influx via the CNG channels. In the ROS plasma membrane, NCKX1 is present as a dimer and is directly associated with the tetrameric CNG channel. The balance of Ca2+ influx via CNG channels and Ca2+ extrusion via NCKX1 results in an elevated cytosolic free Ca2+ concentration in the dark. Absorption of a photon of light by the visual pigment rhodopsin initiates a signal transduction cascade that results in the hydrolysis of cGMP, thus reducing the number of open CNG channels until, at saturating light, all cGMP is reduced to GMP. Thus all CNG channels close which results in the hyperpolarization of the rod plasma membrane. In turn, the continued activity of the light-independent NCKX1 leads to a decrease in the cytosolic Ca2+ concentration, which then leads to the activation of the enzyme guanylyl cyclase, increased synthesis of cGMP, and reopening of CNG channels. This negative feedback loop of Ca2+ regulation of guanylyl cyclase is mediated by a small accessory Ca2+-binding protein named GCAP and is responsible in part of the process of light adaptation. For more detailed reviews see (Palczewski et al. 2000; Fain et al. 2001). Consistent with the critical role of NCKX1 in visual transduction in retinal rod photoreceptors as described above, disruption of the slc24a1 gene in mice results in rod dysfunction and congenital stationary night blindness (Vinberg et al. 2015).
SLC24A Family (K+-Dependent Na+-Ca2+ Exchanger, NCKX), Fig. 1

The role of NCKX1 in phototransduction retinal rod photoreceptors. Depicted are the key proteins involved in visual transduction in vertebrate rod photoreceptors. When rhodopsin absorbs a photon of light, a conformational change occurs, converting rhodopsin to its active form, which in turn activates the heterotrimeric G-protein transducin. The α-subunit of transducin, Gα, activates a phosphodiesterase (PDE) which leads to the hydrolysis of cGMP molecules present in the cytoplasm. This leads to the closure of the CNG channel and stopping the influx of Na+ and Ca2+. NCKX1 proteins continue to remove Ca2+ from the cytoplasm. When Ca2+ levels drop, guanylyl cyclase is activated via the accessory protein GCAP and this restores the levels of cGMP molecules in the cytoplasm and reopens the CNG channels

Functional Analysis Through Gene Deletion Experiments and Through Analysis of Mutations Found in Patients with Congenital Diseases

Few studies have addressed the in situ role of NCKX proteins in tissues by direct measurements of NCKX activity and its effect on cell signaling, except for the role of NCKX1 in retinal rod photoreceptors described above. Most of our current knowledge on the role of NCKX isoforms in various tissues has come from gene deletion studies and studies on the genetic analysis of mutations found in SLC24A genes. Figure 2 highlights the tissue distribution of NCKX proteins and some of the proposed physiological roles. A mutation in the SLC24A1 gene (NCKX1) was found in patients with congenital stationary night blindness type 1-D (CSBN1D) consistent with the mouse study referred to above. Transcripts of SLC24A2 were found in retinal cone photoreceptors and retinal ganglion cells of the human retina (Prinsen et al. 2000) while slc24a2 knockout showed that NCKX2 modulates cone phototransduction in mice (Sakurai et al. 2016). Moreover, NCKX2 is also widely expressed in neurons throughout the brain, particularly in the hippocampus, and slc24a2 knockout in mice was associated with deficits in motor learning and spatial working memory (Li et al. 2006). A significant reduction in Ca2+ flux in cortical neurons and a loss of long-term potentiation (LTP) at the hippocampal Schaffer/CA1 synapses was also observed in these mice. To date, no congenital diseases have been associated with the SLC24A2 (NCKX2) and SLC24A3 (NCKX3) genes, and no gene deletion studies have been reported for NCKX3; however, NCKX3 transcripts have been found in a wide range of tissues including brain, arteries, intestine, and uterus (Kraev et al. 2001). Recent studies have suggested multiple roles of NCKX4 in a range of tissues. Deletion of the slc24a4 gene in mice revealed significant deficits in olfactory responses, suggesting a similar role of NCKX4 in olfaction as found for NCKX2 in cone phototransduction (Stephan et al. 2012), while in another study, slc24a4 gene deletion was reported to result in a reduced weight phenotype in mice caused by melanocortin-4 receptor-dependent satiety (Li and Lytton 2014). Based on this result, the authors propose that Ca2+ signaling through NCKX4 may affect the function of MC4R receptors in the paraventricular nucleus (PVN) of the hypothalamus that regulates behavior and satiety, thus leading to weight loss in these mice. Association studies have suggested that theSLC24A4 gene is a genetic determinant of hair and eye color in European populations, e.g., Sulem et al. (2007). Finally, genetic analysis of patients with amelogenesis imperfecta (AI) have linked AI to three unique SLC24A4 missense mutations (A146V, L436A, and S499C) associated with abnormal enamel formation, and, consistent with a critical role of NCKX4 in enamel formation, these mutations resulted in loss of function when the mutated NCKX4 proteins were expressed in cell lines, reviewed in (Jalloul et al. 2016a). The final member of the SLC24 gene family, SLC24A5 gene, was found to be a skin pigmentation gene in both zebra fish and human; a SNP in both alleles of this gene has been found to be the major genetic determinant for light skin in people of European descent (Lamason et al. 2005; Stokowski et al. 2007). SLC24A5 differs from other members of the SLC24 gene family in that the NCKX5 protein is not trafficked to the plasma membrane and is located within the cell (Lamason et al. 2005; Ginger et al. 2008). SLC24A5 transcripts are mainly found in melanin-rich tissues such as melanocytes in the skin and the retinal pigment epithelium (Lamason et al. 2005). As a member of the NCKX protein family, NCKX5 exhibits a K+-dependent Na+/Ca2+ exchange activity when expressed in cell lines, but it is unclear how the NCKX5 protein affects pigmentation, and to date, NCKX5-mediated Ca2+ transport has yet to be demonstrated in pigmented cells (Szerencsei et al. 2016). Moreover, mutations in the SLC24A5 gene (A115E, S182R, and R174K) have been linked to oculocutaneous albinism (OCA6), and these mutations abolished transport activity when introduced in the homologous residues of the human NCKX4 protein (Jalloul et al. 2016a). One of the main obstacles in addressing physiological roles for NCKX proteins in various tissues is the lack of NCKX-specific inhibitors.
SLC24A Family (K+-Dependent Na+-Ca2+ Exchanger, NCKX), Fig. 2

Tissue distribution and proposed functional roles of mammalian NCKX isoforms. The SCL24A gene family contains five members encoding NCKX1–5

Structure-Function Relationships of NCKX Proteins

After several cDNAs of NCKX proteins, either representing different isoforms or different species, were cloned, their sequence comparison revealed that all NCKX proteins have four domains: (1) an extracellular hydrophilic loop at the N-terminus that contained a glycosylation site as well as a cleavable signal peptide; (2) next a set of five hydrophobic segments thought to be α helical transmembrane segments (TMS) with very short connecting loops; (3) followed by a large hydrophilic loop located in the cytosol; (4) towards the C-terminus another set of five TMS with very short connecting loops and a short C-terminal tail. Topological studies on the NCKX2 protein (as this is the best expressing NCKX cDNA in cell lines) have led to the model illustrated in Fig. 3. These studies also showed that cation transport function was mediated by the two sets of hydrophobic TMS (reviewed in Schnetkamp et al. (2014)). The human NCKX2 cDNA has also been used for most studies that addressed residues within the two sets of TMSs that are important for transport function of NCKX proteins, either by contributing to coordination of Ca2+, K+, and Na+ binding or by mediating conformational changes associated with the alternate access model of cation transport. These studies used a range of different methods to measure NCKX transport function including measurement of 45Ca fluxes, whole cell patch clamp measurements of NCKX currents, and the use of fluorescent fluo-based Ca2+-indicating dyes to measure changes in cytosolic free Ca2+ concentrations mediated by NCKX (reviewed in Schnetkamp et al. (2014)). Figure 4 illustrates the NCKX transport activity measured with fluo-4 in human embryonic kidney 293 (HEK293) cells which were transfected with NCKX2 cDNA. Functional consequences of single residue substitutions covering the entire two α-repeat regions of the NCKX2 protein (∼100 residues) were analyzed to determine their potential contribution to cation coordination (as manifested by shifts in Km) or overall transport rate (as manifested by lowering of Vmax). Twenty-three residue substitutions lowered the Vmax to <20% of that observed for WT NCKX2; these include five acidic residues (E and D) as well as eight polar residues (S, T, and N) that could be involved in cation coordination, but also ten residues that are either glycine, small hydrophobic residues, or proline which may be important for helix-helix contacts and/or helix breaks that are often found in the binding pockets of solute transporters (Winkfein et al. 2003). In subsequent studies, many of the same residue substitutions were found to cause shifts in the Km for all three substrate cations consistent with the alternate access model of transport and the presence of single set of cation-binding sites that can either accommodate four Na+ ions or one Ca2+ plus one K+ ion. Three central acidic residues of particular importance were highlighted in these studies: E188 in the α-1 region and D548 in the α-2 region were identified as the main Ca2+-coordinating residues (Kang et al. 2005a), while D575 in the α-2 region was reported to be critical for K+ binding (Kang et al. 2005b). E188 and D548 are conserved in all NCX and NCKX proteins, while D575 is conserved in all NCKX proteins (while all NCX have an asparagine at the position). More recently, the crystal structure of the archaebacterial Na+/Ca2+ exchanger NCX_Mj has been reported, and the residues homologous to E188 and D548 were shown to be the Ca2+-coordinating residues (Liao et al. 2012). Similarly, in a NCKX2 homology model based on the NCX_Mj crystal structure, bound Ca2+ was found to be coordinated by E188 and D548; moreover, the bound K+ ion was shown to be in direct contact with D575 consistent with the earlier mutagenesis data (Zhekova et al. 2016).
SLC24A Family (K+-Dependent Na+-Ca2+ Exchanger, NCKX), Fig. 3

Topological model of NCKX proteins. The topological model of NCKX membrane proteins is based on experimental studies carried out on NCKX2 (Szerencsei et al. 2013). Because of the high degree of homology in the transmembrane segments of all reported NCKX sequences, it is believed that they share the same topology. (a) NCKX proteins are composed of ten α-helical transmembrane segments (TMS), organized into two 5 TMS clusters joined by a large intracellular hydrophilic loop. Shaded in gray are the α1-repeat (TMS 2–3) and α2 repeat (TMS 7–8) regions. In circles are the approximate locations of the three acidic residues important for cation binding. (b) 3D structure of NCKX2 protein: the proposed three-dimensional structure of NCKXs based on a homology modeling that is based on the crystal structure of the distantly related archaebacterial Na+/Ca2+ exchanger from Methanococcus jannaschii (NCX_Mj) when bound to the Ca2+ (red circle) and K+ (green circle) ion (Zhekova et al. 2016). Highlighted are the three acidic residues important for cation binding at the active site

SLC24A Family (K+-Dependent Na+-Ca2+ Exchanger, NCKX), Fig. 4

NCKX2 proteins’ activity and localization. (a) The transport activity of the myc-tagged NCKX2 proteins when expressed in HEK293 cells. Cells were transiently transfected with NCKX2 pcDNA or were mock transfected (no DNA) and loaded with Fluo-4FF and Na+ as described (Jalloul et al. 2016b). NCKX-mediated Ca2+ influx was initiated by the addition of 0.35 mM CaCl2 and 50 mM KCl, resulting in a steady rise in fluorescence in NCKX2-transfected cells. (b) The images represent expression of NCKX2 in nonpermeabilized(−T)and permeabilized(+T)cells. HEK293 cells were transfected with the myc-tagged-NCKX2 pcDNA and incubated with both the myc and the trans-Golgi network (TGN) marker TGN46 antibodies. Left panel(−T), nonpermeabilized cells show that myc-tagged NCKX2 proteins (green) are expressed on the plasma membrane. Labeling with Ab against the TGN46 (red) was used as a control for the absence of permeabilized or leaky cells. Right panel(+T), cells permeabilized with 0.2% triton X100 show large amounts of NCKX2 proteins present in intracellular organelles and are not limited to the plasma membrane. Unlike intact cells, TGN staining (red) was detected in all permeabilized cells

Summary

The SLC24A gene family encodes five K+-dependent Na+/Ca2+ exchanger proteins (NCKX1–5) that play important roles in Ca2+ signaling in many tissues. Here, we have reviewed the history of their discovery, key functional properties of NCKX proteins, and the well-established physiological role in retinal photoreceptors. Next, we have summarized what has been learned about NCKX physiology through gene deletion experiments in model organisms and through investigation of mutations found in congenital diseases. Finally, we have described our current knowledge about structure-function relationships of NCKX proteins.

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Copyright information

© Springer International Publishing AG 2018

Authors and Affiliations

  • Ali H. Jalloul
    • 1
  • Robert T. Szerencsei
    • 1
  • Tatiana P. Rogasevskaia
    • 1
    • 2
  • Paul P. M. Schnetkamp
    • 1
  1. 1.Department of Physiology and Pharmacology, Hotchkiss Brain Institute, Cumming School of MedicineUniversity of CalgaryCalgaryCanada
  2. 2.Department of BiologyMount Royal UniversityCalgaryCanada