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Cardiovascular Research 2006 71(1):22-29; doi:10.1016/j.cardiores.2006.03.018
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Copyright © 2006, European Society of Cardiology

Cardiac ankyrins: Essential components for development and maintenance of excitable membrane domains in heart

Shane R. Cunhaa and Peter J. Mohlera,b,*

aDepartment of Pathology, Vanderbilt University Medical School, Nashville, TN 37232, United States
bCenter for Molecular Neuroscience, Vanderbilt University Medical School, Nashville, TN 37232, United States

* Corresponding author. Vanderbilt University Medical School, 1161 21st Street South, MCN C3321A, Nashville, TN 37232, United States. Tel.: +1 615 343 5776; fax: +1 615 343 7023. Email address: Peter.j.mohler{at}vanderbilt.edu

Received 13 January 2006; revised 16 March 2006; accepted 20 March 2006


   Abstract
Top
 Abstract
1. Introduction
 2. Ankyrins
 3. Dysfunction in ankyrin-B...
 4. Ankyrin-G is required...
 5. Summary
 References
 
Ankyrins are intracellular proteins required for the biogenesis and maintenance of membrane domains in both excitable and non-excitable cells. Ankyrin family polypeptides have been implicated in the targeting and stabilization of membrane proteins including ion channels, transporters, exchangers and cell adhesion molecules in diverse tissues and cell types including the erythrocyte, kidney, lung and brain. Dysfunction in ankyrin-based pathways has previously been linked to abnormalities in vertebrate physiology including spherocytosis and anemia, ataxia and axonal degeneration. Recent findings have illuminated the importance of ankyrin-based pathways in excitable cells of the heart. Specifically, two ankyrin gene products, 220-kDa ankyrin-B and 190-kDa ankyrin-G, have been implicated in the targeting of structurally diverse membrane ion channels and transporters to excitable membrane domains in cardiomyocytes. Moreover, findings in humans and mice have determined the critical nature of ankyrin-based pathways for normal cardiac excitability. Reduction of ankyrin-B expression levels in mice or the presence of ankyrin-B loss-of-function mutations in humans leads to ‘ankyrin-B syndrome’, a cardiac disease with a spectrum of clinical presentations including bradycardia, ventricular tachycardia and sudden cardiac death in response to catecholaminergic stimuli. Ankyrin-G is required for expression of the major cardiac voltage-gated Nav channel, Nav1.5, at specialized cardiac membrane domains. Human variants in SCN5A (encodes Nav1.5) that block Nav1.5 interaction with ankyrin-G lead to loss of Nav1.5 membrane expression and Brugada syndrome. Together, these recent findings in heart reinforce the importance of ankyrin-based pathways for normal vertebrate physiology and raise exciting new questions regarding the cellular roles for ankyrin polypeptides in cardiac and other excitable cells. While ankyrins have only been recently identified in heart, our current understanding suggests that elucidating the roles of ankyrins in organizing and targeting protein complexes to excitable membrane domains will yield important insights into the molecular basis of cardiac arrhythmias.

KEYWORDS Ankyrin; Arrhythmia; Long QT syndrome; Brugada syndrome; Cytoskeleton


   1. Introduction
Top
 Abstract
 1. Introduction
2. Ankyrins
 3. Dysfunction in ankyrin-B...
 4. Ankyrin-G is required...
 5. Summary
 References
 
Understanding the molecular mechanisms underpinning cardiac arrhythmias has been an active area of cardiovascular research for the past 25 years. Much of this research has focused on characterizing the constituents of ion channels, transporters and receptors that regulate the movement of ions as it relates to the progression of the cardiomyocyte action potential [1]. Recent studies have illuminated the critical role of ion channel/transporter trafficking and stability for normal cardiac function. Specifically, dysfunction in ankyrin proteins, which likely serve both channel/transporter scaffolding and cellular chaperone functions, has been implicated in the biogenesis of human arrhythmia.


   2. Ankyrins
Top
 Abstract
 1. Introduction
 2. Ankyrins
3. Dysfunction in ankyrin-B...
 4. Ankyrin-G is required...
 5. Summary
 References
 
Ankyrins are a family of intracellular proteins that organize, transport and anchor membrane protein complexes to the actin/spectrin cytoskeleton, thereby creating microdomains within membranes with distinct functional properties. Diversity within the ankyrin family arises from three independent genes (ANK1, ANK2 and ANK3) that encode canonical ankyrin polypeptides and various alternative splice variants. ANK1 on human chromosome 8p11 encodes ankyrin-R (R for restricted expression), which is expressed in erythrocytes and a subset of muscles and neurons [2–4]. ANK2 on human chromosome 4q25–27 encodes ankyrin-B (B for broadly expressed), which is ubiquitously expressed [5]. ANK3 on human chromosome 10q21 encodes ankyrin-G (G for giant size and general expression), which also has ubiquitous expression [6–8]. Alternative splice variants of all three ankyrin polypeptides have been identified; some of which have distinct subcellular localization and functional properties [9–12] (see Fig. 1). While the heart expresses different isoforms of both ankyrin-B and ankyrin-G, differences in the regional expression or subcellular localization of these polypeptides has not yet been determined [13–16].


Figure 1
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  		Fig. 1 Ankyrin gene products display striking diversity in domain organization and tissue/subcellular expression. Fig. 1 represents domain organization, observed molecular weight and tissue distribution of specific ankyrin gene products. Labels for the ankyrin membrane-binding domain (MBD), spectrin-binding domain (SBD), death domain (DD), C-terminal domain (CTD), tail domain, serine-rich domain and unique domains are depicted on the bottom left of the figure. Due to space limitations, not all identified ankyrin polypeptides have been included.

 
Canonical ankyrins have four distinct domains: a membrane-binding domain, a spectrin-binding domain, a death domain and a C-terminal domain (see Fig. 2). Together, the death domain and C-terminal domain comprise the ‘regulatory’ domain. The membrane-binding domain, consisting of 24 ANK repeats, is organized in a contiguous spiral stack [17]. Contrary to its label, the membrane-binding domain does not directly bind cell membranes, but instead binds to a variety of membrane proteins including ion channels, transporters and cell adhesion molecules (reviewed in [18,19]). Ankyrin membrane-binding domain interactions are mediated by the ANK repeats, which form stacks of anti-parallel {alpha}-helices linked by β-hairpin loop tips arranged perpendicular to the {alpha}-helices [20]. Similar to other ANK repeat-containing proteins, it is thought that within these exposed loop tips resides the specificity for protein interactions with ankyrins [20]. For example, the inositol 1,4,5-trisphosphate (IP3) receptor interacts with the β-hairpin loop tips of ANK repeats 22–24 on 220-kDa ankyrin-B [21].


Figure 2
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  		Fig. 2 Canonical ankyrin domain organization. Twenty-four ANK repeats reside within the membrane-binding domain and mediate protein–protein interactions. The amino terminus of the 62-kDa spectrin-binding domain binds to spectrin, thereby tethering ankyrin to the cytoskeleton. The functional significance of the death domain has yet to be characterized. The C-terminal domain modulates protein–protein interactions and targets ankyrin-associated proteins to subcellular domains. Together, the death and C-terminal domains comprise the ‘regulatory’ domain.

 
The ankyrin membrane-binding domain is multivalent and, accordingly, can bind to multiple membrane proteins simultaneously to form large membrane protein complexes. For example, the membrane-binding domain of ankyrin-R has two distinct binding sites for the anion exchanger (functionally expressed as a dimer) such that ankyrin-R can be simultaneously bound by two dimers of the anion exchanger [22]. The membrane-binding domain of ankyrin-R also has two binding sites for the L1 cell adhesion molecule (L1CAM) neurofascin [23]. These binding sites mediate interactions of ankyrin-R with dimers of the anion exchanger, neurofascin alone or neurofascin plus the anion exchanger [22,23]. Ankyrin-B also has multivalent binding properties, organizing the formation of a complex consisting of the Na+/Ca2+ exchanger, the Na+/K+ ATPase and the IP3 receptor [24].

The central region of the canonical ankyrin contains a 62-kDa spectrin-binding domain (SBD), which mediates interactions between ankyrin and the spectrin/actin-based cytoskeleton. In fact, ankyrins were initially identified based on their ability to bind spectrin in the erythrocyte membrane [25]. Early notions suggested that this interaction functioned solely to link ankyrin and associated integral membrane proteins to the underlying cytoskeleton, but recent studies have demonstrated a greater degree of reciprocity between ankyrin and β-spectrin where by ankyrins may assist in the formation and/or maintenance of the spectrin/actin cytoskeleton. In cases of hereditary spherocytosis associated with mutations in ankyrin-R, erythrocytes display reduced spectrin levels [26–28]. In addition, β4-spectrin levels are decreased following disruption of ankyrin-G expression in cerebellar neurons [29]. Specifically, β-spectrin levels were diminished in the axon initial segment, a region that displays ankyrin-G and β-spectrin co-localization [29]. In cardiomyocytes, the interaction between β2-spectrin and ankyrin-B is necessary for the appropriate localization of β2-spectrin to intracellular striated compartments overlying the M-line [30]. Surprisingly, this interaction is not required for ankyrin-B-dependent targeting of the IP3 receptor [30]. Exciting new insights into the ankyrin/spectrin relationship were gained by a recent study that used small interfering RNA to inhibit expression of human ankyrin-G in human bronchial epithelial cells [31]. In particular, Kizhatil and Bennett found that inhibition of ankyrin-G expression reduced β2-spectrin levels in the lateral membrane domains of these epithelial cells. Not only was there an absence of ankyrin-G and β2-spectrin under these conditions, there was almost a complete loss of lateral membrane domains [31]. This study is the first to suggest that in addition to targeting and organizing protein complexes, ankyrin polypeptides are critical for the biogenesis of entire membrane domains. Ankyrins clearly assist in the targeting of spectrin to the cytoskeleton, but other mechanisms may also assist in this process. For example, β-spectrin may incorporate into the cytoskeleton via its association with phosphatidylinositol lipids [32] or {alpha}-catenin [33]. Once spectrin is localized to the cytoskeleton, it most likely plays an important role in retaining ankyrin and ankyrin-associated proteins at the cytoskeleton. For example, in mice lacking β4-spectrin, ankyrin-G levels are reduced at the nodes of Ranvier and axon initial segments [34].

In addition to the membrane-binding domain and the spectrin-binding domain, ankyrins harbor a 90-amino acid death domain with unknown function. While death domains may facilitate self-association between homotypic and heterotypic proteins, the death domains of ankyrin-B do not homo-dimerize with significant affinity [35]. However, the death domain of ankyrin-G has been shown to interact with the pro-apoptotic molecule Fas in kidney tubules [36]. Interestingly, over-expression of this death domain in cultured renal epithelial cells promoted Fas-mediated apoptosis suggesting that ankyrins may function to modulate apoptosis [36].

Of the four domains within ankyrin, the C-terminal domain is the most divergent between ankyrin gene products. For example, there is only 11% amino acid identity between the C-terminal domains of ankyrin-B and ankyrin-G, while there is 74% amino acid identity between their membrane-binding domains [37,38]. The ankyrin C-terminal domain is critical for modulating ankyrin gene product function. For example, an alternative splice variant of ankyrin-R lacking 161 residues within its regulatory domain has a higher affinity for spectrin and the anion exchanger than its full-length counterpart (see Fig. 1) [39]. A polypeptide corresponding to these 161 residues bound to the splice variant and reduced its binding affinity for the anion exchanger [40]. These findings suggest that the C-terminal regulatory domain of ankyrin-R interacts with other ankyrin domains to negatively regulate intermolecular interactions. Further proof for ankyrin intramolecular interactions emerged recently in a report by Abdi and colleagues using the C-terminal domain of ankyrin-B. Specifically, the C-terminal regulatory domain of ankyrin-B was shown to interact with the first ANK repeat within the ankyrin-B membrane-binding domain [35]. Furthermore, this interaction was necessary to rescue normal localization of the IP3 receptor in ankyrin-B+/ – cardiomyocytes [35]. Interestingly, this interaction was not necessary for the IP3 receptor to bind to ankyrin-B, consistent with previous observations that the IP3 receptor binds to ANK repeats 22–24 in the membrane-binding domain [21]. Together, these findings suggest that ankyrin intramolecular interactions play key roles in modulating ankyrin activity.

Ankyrin intermolecular interactions may also play key roles for ankyrin regulation in vivo. For example, a previous study using chimeric constructs that exchanged various functional domains between ankyrin-B and ankyrin-G demonstrated the specificity of the ankyrin-B regulatory domain in rescuing IP3 receptor localization to cardiomyocyte subcellular domains [41]. Furthermore, it has been demonstrated that the molecular co-chaperone human DnaJ homologue 1 (Hdj1/Hsp40) selectively binds to the C-terminal domain of ankyrin-B, but not to that of ankyrin-G [42]. These findings suggest that co-chaperone proteins may recruit and regulate ankyrin protein-binding partners. Finally, ankyrin C-terminal domains have been associated with other large proteins including obscurin [43,44]. Obscurin is an ~800-kDa protein that binds to titin and is involved in the origination of M-lines and the formation of A-bands [45–48]. Therefore, this interaction may play an important role in organizing ankyrin and ankyrin-associated proteins to specific subcellular domains within cardiomyocytes. Alternatively, ankyrins may play key roles in the localization of obscurin and biogenesis of key cardiac membrane domains.

The most compelling evidence that the C-terminal domain modulates ankyrin function has been reported in studies that associate cardiac arrhythmias, such as ‘ankyrin-B syndrome’, with loss-of-function mutations in the C-terminal domain of ankyrin-B. These findings will be presented in the following section.


   3. Dysfunction in ankyrin-B and human arrhythmia
Top
 Abstract
 1. Introduction
 2. Ankyrins
 3. Dysfunction in ankyrin-B...
4. Ankyrin-G is required...
 5. Summary
 References
 
Long QT syndrome (LQTS) is a multi-loci congenital (and acquired) disorder characterized by a prolonged rate corrected QT interval (QTc) inducing syncope and risk of sudden death. The heterogeneous mutations that give rise to this syndrome either increase the inward-depolarizing current or decrease the outward-repolarizing current of the cardiomyocyte (reviewed in [49]). Concomitantly, these mutations disrupt the subunits of the sodium channel (SCN5A–LQT3) or the potassium channel (or associated subunits; KCNQ1–LQT1, KCNH2–LQT2, KCNE1–LQT5, KCNE2–LQT6). In 1995, a novel locus for LQTS was identified in a French family that was initially referred to physicians following two instances of sudden death [50]. In contrast to other LQTS phenotypes, the phenotype manifested in this family had an uncommon T-wave morphology with polyphasic features and severe sinus node bradycardia (usually less than 50 beats/min), which precipitated atrial fibrillation. Of the 56 surviving family members, 21 individuals exhibited ventricular repolarization abnormalities, which were highly suggestive of LQTS. While all 21 patients demonstrated persistent elevated QTc despite normalization of their atrial rates, only a few of them manifested paroxysmal atrial fibrillation. A novel locus associated with this type of LQTS was found on human chromosome 4q25–27 [50]. Eight years later, this locus was found to reside within the human ANK2 gene, which encodes ankyrin-B [51]. This case study was the first instance of LQTS arising from a mutation in a protein other than a sodium or potassium channel (or channel subunit). Subsequent analysis demonstrated that this type of LQTS (atypical type 4) was associated with a mis-sense mutation (A to G at position 4274 in ANK2 exon 36 resulting in E1425G) in the C-terminus of the spectrin-binding domain of 220-kDa ankyrin-B (see Fig. 3) [51].


Figure 3
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  		Fig. 3 ANK2 variants. To date, 15 mis-sense mutations have been identified in ANK2 [52,53]. The mutations are grouped according to their association with cardiac dysfunction (asymptomatic and/or symptomatic). Loss-of-function variants are denoted with an asterisk. Italicized variants have yet to be analyzed in cardiomyocytes.

 
The human phenotype associated with loss-of-function mutation in ankyrin-B is well mimicked in mice heterozygous for a null mutation in Ank2 (ankyrin-B+/ – mice). Ankyrin-B+/ – mice display bradycardia, intermittent isorhythmic atrioventricular dissociation and prolonged QTc intervals. In addition, ankyrin-B+/ – mice experience syncope and death following significant catecholaminergic stimuli, similar to humans that experience sudden cardiac death following physical exertion and/or emotional stress [51]. At the cellular level, single ankyrin-B+/ – cardiomyocytes display delayed after-depolarizations (DAD) and early after-depolarizations (EAD) in response to catecholaminergic stimuli, most likely due to a rise in sarcoplasmic reticulum calcium concentrations [51]. Mechanistically, the increase in intracellular calcium is, in part, the result of decreased expression and mis-localization of the IP3 receptor, Na+/K+ ATPase and Na+/Ca2+ exchanger. Decreased expression of Na+/K+ ATPase would precipitate elevated intracellular sodium concentrations, which in turn would check calcium-export mediated by the Na+/Ca2+ exchanger. The normal calcium-buffering capacity of the sarcoplasmic reticulum would falter in the presence of elevated intracellular calcium leading to elevations in sarcoplasmic reticulum calcium transients and extrasystoles.

Ankyrin-B coordinates the formation of a complex consisting of the IP3 receptor, Na+/K+ ATPase and the Na+/Ca2+ exchanger [24]. Accordingly, introduction of an ankyrin-B GFP construct into ankyrin-B+/ – cardiomyocytes rescues expression and localization of these three proteins to the T-tubule/sarcoplasmic reticulum junctions [52]. In contrast, an ankyrin-B GFP construct harboring the E1425G mutation is incapable of rescuing the normal expression and localization pattern of these proteins [51]. Furthermore, this loss-of-function mutant inhibits direct interactions of ankyrin-B with the IP3 receptor, Na+/K+ ATPase and the Na+/Ca2+ exchanger [24]. Interestingly, haploinsufficiency of ankyrin-B selectively effects ankyrin-B localization at T-tubules and intercalated discs, but not over the M-line suggesting that ankyrin-B may exist in spatially distinct subpopulations [24].

Since the initial characterization of E1425G in atypical long QT syndrome type 4, four additional loss-of-function mutations have been identified within the spectrin-binding and regulatory domains of ankyrin-B (see Fig. 3). These mutations result in diverse clinical presentations. Phenotypes associated with probands harboring ANK2 variants include bradycardia, sinus arrhythmia, delayed conduction/conduction block, idiopathic ventricular fibrillation and catecholaminergic polymorphic ventricular tachycardia. However, the penetrance of ankyrin-B mutations is not complete and many carriers are asymptomatic [52,53], but are presumably at higher risk for cardiac events. Since many of the probands with ANK2 loss-of-function variants (particularly those without E1425G variant) do not necessarily display a prolonged QT interval, we have proposed the term of ‘ankyrin-B syndrome’ rather than type 4 long QT syndrome to more accurately encompass the clinical cardiac phenotypes associated with ankyrin-B loss-of-function mutations. The significance of ANK2 loss-of-function variants in the context of non-cardiac tissues has not yet been addressed. Based upon the global distribution of ANK2 in excitable and non-excitable tissues, we predict that carriers of ANK2 variants may display non-cardiac defects. In fact, based on the characterized neural abnormalities in mice with reduced ankyrin-B expression [14], ANK2 loss-of-function variant carriers may potentially display mild neurological disease.

Human ANK2 variants may interfere with normal ankyrin-B activity by modulating its intermolecular interactions. Recent findings demonstrate that the severe E1425G variant affects binding of the Na+/K+ ATPase, IP3 receptor and the Na+/Ca2+ exchanger with the mutant ankyrin [24]. Moreover, the R1788W variant may lead to ankyrin-B loss-of-function by interfering with ankyrin-B binding to Hdj1/Hsp40 [42]. Therefore, human mutations that affect ankyrin-B intermolecular interactions may lead to mis-localization of ankyrin-associated integral proteins, thereby disrupting normal cardiomyocyte excitability. In principle, C-terminal human mutations may also disrupt interdomain interactions, although there currently are no known examples.


   4. Ankyrin-G is required for development and maintenance of excitable membrane domains in heart
Top
 Abstract
 1. Introduction
 2. Ankyrins
 3. Dysfunction in ankyrin-B...
 4. Ankyrin-G is required...
5. Summary
 References
 
Brugada syndrome is characterized by abnormal electrocardiogram (ECG) findings with an increased risk for sudden cardiac death. The abnormal ECG criteria include an elevated ST interval in the precordial leads associated with right bundle branch block and T-wave inversion [54]. Transient normalization of ECG may be observed, but administration of sodium channel blockers such as flecainide, procainamide or ajmaline reveal characteristic ECG traces such as prolonged QRS intervals [55]. Lengthening of this interval is indicative of conduction slowing, which is a symptom of Brugada syndrome. Sudden cardiac death usually occurs at night and is the result of ventricular fibrillation [49].

Brugada syndrome is an autosomal-dominant disorder that commonly arises from heterogeneous mutations that disrupt the inward depolarizing sodium current [56]. Mutations to SCN5A, the {alpha} subunit of the voltage-gated sodium channel, account for less than 30% of the cases of Brugada syndrome [57]. Most mutations affect the biophysical properties of this channel, thereby reducing inward sodium current. These mutations may alter the gating properties of the channel, the structure of the ion-conducting pore or the rate of channel inactivation. However, an alternative hypothesis is that decreased expression of these channels at their proper location within excitable membrane domains of the heart would reduce normal sodium current.

A recent study identified a mis-sense variant (G3157A leading to E1053K) in the human sodium channel (Nav1.5) that significantly reduces expression of this channel at T-tubules and intercalated discs in ventricular cardiomyocytes [13]. This variant is located in the nine amino acid ankyrin-binding motif in the DII–DIII loop, which is highly conserved among voltage-gated sodium channel isoforms including Nav1.1, Nav1.2, Nav1.4, Nav1.5 and Nav1.6 [58,59]. The Nav1.5 E1053K variant disrupts association between Nav1.5 and ankyrin-G, thereby significantly reducing expression of the channel at the membrane surface [13]. Consistent with these findings, completely removing the ankyrin-binding motif in Nav1.5 eliminates ankyrin-G association with the sodium channel in vitro [13]. Interestingly, the Nav1.5 E1053K mutation has no effect on Nav1.5 expression at the plasma membrane of HEK293 cells, suggesting that the channel is not mis-folded or rendered unstable by this mutation [13]. While expression of the mutant channel was normal in HEK293 cells, the biophysical properties of the channel were altered. In particular, the threshold for channel activation was more negative than that of wild-type. In addition, channel inactivation occurred faster and recovered slower for the mutant channel [13]. One exciting way of interpreting these results is that ankyrin-G not only regulates the trafficking of Nav1.5, but also modulates the biophysical properties of Nav1.5 once at the membrane surface [13]. Alternatively, the Nav1.5 E1053K variant may affect the inherent biophysical properties of the channel independent of ankyrin-G activity. These alternative interpretations may be resolved by an experimental system where Nav channel targeting/biophysics can be analyzed in conditions where ankyrin-G can be selectively inhibited and then re-introduced.

Many parallels can be drawn between the actions of ankyrin-G in cardiomyocytes and neural tissue. Similar to its actions in cardiomyocytes, ankyrin-G targets Nav channels to areas of increased membrane excitability in neurons such as the axon initial segments (AIS) and nodes of Ranvier [29,60,61]. Consistent with these findings, ankyrin-G co-localizes with Nav channels in the brain and at neuromuscular junctions [62–64]. In addition, ankyrin-G co-purifies with Nav channels from the brain [8,65]. Similar to the cardiac isoform of ankyrin-G, the neural isoforms of ankyrin-G (270 and 480 kDa) interact with the Nav channel via the highly conserved ankyrin-binding motif found in the DII–DIII loop of the Nav channels [58,59]. The clustering of ankyrin-G and Nav channels at the AIS appears to be mediated by cell-autonomous factors [66], while protein clustering at the nodes of Ranvier involves interactions with glial cells [66,67]. Many domains of ankyrin-G are involved in restricting its localization to excitable membrane domains including the serine-rich domain found only in the neural isoforms of ankyrin-G [60]. The insertion of this domain along with a variable ‘tail’ domain in between the SBD and DD distinguishes the neural isoforms from the cardiac isoforms of ankyrin-G (see Fig. 1). In addition to targeting Nav channels, ankyrin-G also localizes β4-spectrin and neurofascin to excitable membrane domains in neurons [29]. Accordingly, mice with cerebellar-specific knock-outs of ankyrin-G display inappropriate localization of Nav, β4-spectrin and neurofascin [60]. These knock-out mice exhibit ataxia and abnormal action potentials, which most-likely arise from abnormal interneuronal circuitry. Finally, a recent study also demonstrated the importance of ankyrin-G in establishing a subcellular gradient of neurofascin across the soma and AIS of Purkinje cells [68]. This gradient provided directional cues for the axons of basket cells such that they appropriately targeted and synapsed on the AIS of Purkinje cells [68]. Findings from these studies in neural tissue provide valuable insight to our general understanding of ankyrins and how they may function in other excitable cells such as cardiomyocytes.


   5. Summary
Top
 Abstract
 1. Introduction
 2. Ankyrins
 3. Dysfunction in ankyrin-B...
 4. Ankyrin-G is required...
 5. Summary
References
 
Studies over the past twenty five years have revealed the importance of ankyrins from the red blood cell to the brain and other excitable tissues including the heart. Findings that link dysfunction in ankyrin-based pathways to human disease further illuminate the significance of ankyrins to normal metazoan physiology. Recent studies in the heart have expanded the potential roles for ankyrins as not just simple membrane scaffolds, but as much more dynamic chaperone/regulatory proteins which may be required for the active trafficking, stability and regulation of structurally diverse membrane proteins. Indeed, results from Kizhatil and Bennett would suggest that these proteins are required for the biogenesis of entire membrane domains [31]. While great strides have been accomplished in ankyrin research, we have just begun to uncover the great diversity and complexity of functions bound to be associated with ankyrins.

Please note that Refs. [69–78] are cited in Fig. 1.


   Acknowledgements
 
This work was supported by NIH grant 1R01HL083422 to PJM. SRC was supported by the Vanderbilt Post-doctoral Training Program in Neurogenomics (T32 MH065215).


   Notes
 
Time for primary review 35 days


   References
Top
 Abstract
 1. Introduction
 2. Ankyrins
 3. Dysfunction in ankyrin-B...
 4. Ankyrin-G is required...
 5. Summary
 References
 

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