Disease relevance of ANK3

• Human gene mutations, which affect ankyrin-G-based pathways for voltage-gated Na(v) channel localization, are associated with Brugada syndrome, a second potentially fatal arrhythmia [1].
• The painful neuromas exhibited considerably higher levels of ankyrin G [2].
• Ankyrin G overexpression in Hutchinson-Gilford progeria syndrome fibroblasts identified through biological filtering of expression profiles [3].
• CONCLUSION: Our results may represent the first evidence for abnormally increased levels of ankyrin G protein with painful neurofibromas [4].
• Elevated ankyrin G in a plexiform neurofibroma and neuromas associated with pain [4].

High impact information on ANK3

• Conversely, in ankyrin-G-null neurons, betaIV-spectrin is not localized to these sites [5].
• [Beta]IV-spectrin regulates sodium channel clustering through ankyrin-G at axon initial segments and nodes of Ranvier [5].
• Nav1.5 E1053K mutation causing Brugada syndrome blocks binding to ankyrin-G and expression of Nav1.5 on the surface of cardiomyocytes [6].
• These data suggest that Na(v)1.5 associates with ankyrin-G and that ankyrin-G is required for Na(v)1.5 localization at excitable membranes in cardiomyocytes [6].
• Spectrin binds both Ank1 and Ank3 avidly, as expected [7].

Biological context of ANK3

• We have localized ANK3 to human Chromosome 10q21 by fluorescence in situ hybridization [8].
• Lateral membrane biogenesis in human bronchial epithelial cells requires 190-kDa ankyrin-G [9].
• Ankyrin-G polypeptides are required for restriction of voltage-gated sodium channels, L1 cell adhesion molecules, and beta IV spectrin to axon initial segments and are believed to couple the Na/K-ATPase to the spectrin-actin network at the lateral membrane in epithelial cells [9].
• We report here that depletion of 190-kDa ankyrin-G in human bronchial epithelial cells by small interfering RNA results in nearly complete loss of lateral plasma membrane in interphase cells, and also blocks de novo lateral membrane biogenesis following mitosis [9].
• Furthermore, other genes that co-clustered with ANK3 might provide mechanistic clues regarding senescence in cultured HGPS cells [3].

Anatomical context of ANK3

• These results demonstrate that 190-kDa ankyrin-G plays a pleiotropic role in assembly of lateral membranes of bronchial epithelial cells [9].
• These results indicate that betaIV-spectrin and ankyrin-G mutually stabilize the membrane protein cluster and the linked membrane cytoskeleton at AIS and NR [5].
• Mice homozygous for the mutation exhibit tremors and contraction of hindlimbs. betaIV-spectrin expression is mostly restricted to neurons, where it colocalizes with and binds to ankyrin-G at axon initial segments (AISs) and nodes of Ranvier (NR) [5].
• A propensity to overexpress ankyrin G after peripheral nerve trauma may turn out to be a factor in the development of painful neuromas and neuropathic pain [2].
• However, smaller isoforms of Ank3 lack the membrane domain and are localized to late endosomes and lysosomes [10].

Associations of ANK3 with chemical compounds

• Cardiomyocytes from ankyrin-B (-/-) mice display mis-localization of inositol 1,4,5-trisphosphate receptors and ryanodine receptors along with reduced contraction rates that can be rescued by expression of green fluorescent protein (GFP)-ankyrin-B but not GFP-ankyrin-G [11].
• In this report, we describe a new phosphotyrosine-independent p85 SH2-binding protein, ankyrin 3 (Ank3) [10].
• The ammonium transporter RhBG: requirement of a tyrosine-based signal and ankyrin-G for basolateral targeting and membrane anchorage in polarized kidney epithelial cells [12].
• (i) RhBG and ankyrin-G were colocalized in vivo in the basolateral domain of epithelial cells from the distal nephron by immunohistochemistry on kidney sections [12].
• Chloroquine, an inhibitor of lysosomal-mediated degradation pathways, blocked the ability of Ank3 to enhance PDGFR degradation [10].

Physical interactions of ANK3

• Expression of chimeras between the two isoforms of ankyrin suggests that the membrane-binding domain of ankyrin-G is critical for reducing the Ina-p of Nav1 [13].

Other interactions of ANK3

• Moreover, analysis of rat 190-kDa ankyrin G/ankyrin B chimeras shows that all three domains of 190-kDa ankyrin-G are required for preservation of the lateral membrane [9].
• Human 220-kDa ankyrin-B, a closely related ankyrin isoform, is incapable of preserving the lateral membrane following 190-kDa ankyrin-G depletion [9].
• Ankyrin-G associates with the principal voltage-gated Na channel in the heart, and loss of this interaction due to mutation of Nav1.5 results in Brugada syndrome [14].
• A number of genes reported to regulate neural differentiation and function (i.e. NRP1, ANK3, and CHAT) were found under these linkage peaks and may influence the levels of neural activity occurring in individuals participating in a spatial working-memory task [15].
• In this study, we explored whether ankyrin-G has a role in modifying gating properties of the neuronal Nav1.6 channel that is predominantly localized at nodes of Ranvier and initial segments [13].

Analytical, diagnostic and therapeutic context of ANK3

• The increased mRNA expression in HGPS cells that was seen for one gene defined using this strategy-namely ANK3- was validated using quantitative reverse-transcriptase amplification, Western analysis and immunofluorescence microscopy, all of which showed significantly increased ankyrin G expression [3].
• METHODS: First, frozen sections of nine nerve specimens obtained from six patients (six nonpainful neuromas, one painful neuroma, and two normal nerves) were immunocytochemically screened for ankyrin G by using confocal laser scanning microscopy [2].
• Findings support results from animal models that link ankyrin G with clustering of sodium channels at axon tips of unmyelinated, sprouting fibers [16].
• Computerized densitometry was used to quantitate ankyrin G expression by comparing band intensities [2].
• Western blot analysis detected ankyrin G, which was visualized by applying the enhanced chemiluminescence technique [2].

References