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Cardiovascular Research 1999 42(2):318-326; doi:10.1016/S0008-6363(99)00063-2
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Copyright © 1999, European Society of Cardiology

From genes to channels: normal mechanisms

Dan M. Rodena,* and Sabina Kupershmidtb

aDepartment of Medicine, Vanderbilt University School of Medicine, Nashville, TN 37232, USA
bDepartment of Pharmacology, Vanderbilt University School of Medicine, Nashville, TN 37232, USA

dan.roden{at}mcmail.vanderbilt.edu

* Corresponding author. Tel.: +1-615-322-0067; fax: +1-615-343-4522

Received 6 October 1998; accepted 4 February 1999


   Abstract
Top
 Abstract
1 Introduction
 2 Genes that determine...
 3 Control of gene...
 4 Summary
 References
 
Electrophysiologic remodeling is a process whereby heart disease alters the electrophysiologic properties of cardiac tissue. These alterations, in turn, can cause or exacerbate disease-related arrhythmias. Ion channels are the fundamental molecular units underlying cardiac electrophysiology, and it therefore follows that electrophysiologic remodeling represents alterations in the function or expression of genes encoding ion channels or other proteins crucial for cardiac electrophysiologic activity. This review will describe the mechanisms whereby normal function of these proteins arises from the processes of gene transcription, mRNA processing, and protein transport, post-translational modification, assembly with other proteins, and degradation. Identification of entirely novel targets for drug intervention should result from further understanding of the fundamental mechanisms underlying remodeling.


   1 Introduction
Top
 Abstract
 1 Introduction
2 Genes that determine...
 3 Control of gene...
 4 Summary
 References
 
Diversity in the electrophysiologic properties of cardiac tissue is a normal phenomenon: it is well-recognized that action potentials and propagation vary as a function of specific region and during development. Moreover, it is widely appreciated that the perturbations in control of the action potential duration and its propagation, that characterize diseased tissue, are the proximate causes of arrhythmias. Thus, a major advance in understanding the fundamental mechanisms underlying these changes has been the cloning of genes whose expression results in ion channels and other important proteins that determine cardiac electrophysiology. This information now allows the characteristic electrophysiologic changes observed in conditions such as heart failure, atrial fibrillation, or ischemia to be reinterpreted in a modern molecular context. It is reasonable to assume that the phenomenon of electrophysiologic remodeling – the theme of this issue of Cardiovascular Research – reflects disease-related abnormal expression or function of these genes and that these changes, in turn, cause arrhythmias. Such abnormal gene expression or function can arise as a result of the disease process itself; it is also increasingly recognized that arrhythmias, once initiated, can themselves provide signals to further modify the arrhythmogenic substrate and to thereby exacerbate or perpetuate the arrhythmias. This is succinctly stated in the title of the now-classic report that described this phenomenon, ‘atrial fibrillation begets atrial fibrillation’ [1]. Clearly the hope is that understanding the molecular mechanisms underlying the remodeling process will lead to insights not only into normal electrophysiology, but also to identification of entirely novel targets for pharmacologic intervention. It is the goal of this review to present an overview of normal mechanisms whereby genes encoding ion channels or other proteins determine the normal electrophysiologic properties of the heart, and to identify control points at which these processes may be perturbed in disease. Subsequent manuscripts present a comprehensive view of normal and abnormal physiology of specific channels and diseases.


   2 Genes that determine cardiac electrophysiology
Top
 Abstract
 1 Introduction
 2 Genes that determine...
3 Control of gene...
 4 Summary
 References
 
Implicit in the concept of remodeling is the idea that expression of ion channels genes or the function of their protein products is altered in disease. The genes encoding the major structural proteins ({alpha}-subunits) of ion channels expressed in the heart are listed in Table 1. While the table would suggest that the genes underlying most ion currents in the heart have been cloned, it should be recognized that there is considerable cell-to-cell diversity in the function of recognized ion currents. Although this diversity may reflect processes (discussed further below) such as heteromerization, assembly with ancillary subunits, post-translational modification, or the presence of alternatively spliced or edited mRNA transcripts, the formal possibility remains that genes encoding additional or alternative {alpha}-subunits still remain to be cloned.


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  		Table 1 Human cardiac ion channel genes

 
Expression of a single gene, SCN5A, in heterologous systems is sufficient to recapitulate the cardiac sodium current [2,3]. As Balser points out in his review, closely-related sodium channel {alpha}-subunits (products of different genes) in brain are associated with lower molecular weight subunits, β1 and β2 [4]. These have been cloned and while they can be shown to modulate function of heterologously expressed brain {alpha}-subunits in vitro [5,6], and β1 is expressed in heart, [7] their role in modulating function of the cardiac {alpha}-subunit in vivo remains controversial [8–10]. Genes encoding L- and T-type calcium channel {alpha}-subunits have been isolated [11,12] along with their ancillary ({alpha}–{delta} and β) subunits [13,14].

While sodium and calcium channel {alpha}-subunits are large proteins that are capable of forming functional ion channels without associating with other proteins, the situation is different for potassium channels, as further described by Snyders in this issue. Overwhelming evidence, including crystallographic data [15,16], indicates that potassium channels assemble as multimers of {alpha}-subunits: tetramers for the Kir (inward rectifier) family and Shaker-like voltage-gated channels, and probably dimers for the twin-pore channels [17,18]. It is also clear that heteromeric potassium channel complexes can readily form and that these have electrophysiologic properties distinct from those seen with homomeric assembly of the same subunits. Thus, for example, Kv1.4–Kv1.2 coexpression in Xenopus oocytes results in potassium currents with properties typical of neither Kv1.4 nor Kv1.2 when expressed alone [19]. While this sort of experiment does not address the question of whether such heteromeric {alpha}-subunit assembly actually occurs in vivo, co-immunoprecipitation experiments have demonstrated tight association between Kv1.4 and Kv1.2 channels in brain [20]. A further piece of evidence for heteromeric assembly in vivo comes from studies of alternatively spliced isoforms of HERG, discussed further below. Here, the current seen with coexpression of different {alpha}-subunits (in this case, alternatively spliced products of the same gene) more closely resembles that recorded in native tissue than currents observed when the isoforms are expressed alone [21–23]. Similarly, IK–ACh likely reflects GIRK1–GIRK4 (Kir3.1–Kir 3.4) heterotetramers [24].

A further complicating issue with respect to potassium channels is the identification of multiple ancillary subunits [25–27]. Again, the situation here is that while coexpression of {alpha} and β-subunits in heterologous systems such as Xenopus oocytes can lead to dramatic changes in current amplitude, channel gating, or response to interventions that stimulate intracellular signaling [28–30], the extent to which these phenomena occur in the human heart remains largely unexplored. There seems little doubt that KvLQT1 must be coexpressed with an ancillary β-subunit, minK, to recapitulate IKs [31,32] and, as with HERG, alternatively spliced KvLQT1 isoforms may also play a role [33,34]. Similarly, recapitulation of the ATP-inhibited K+ current IK–ATP requires coexpression of Kir6.1 or 6.2 with the sulfonylurea receptor (SUR) [35,36]. SUR is a 12-membrane spanning ‘subunit’ which is a member of the superfamily of ATP-binding cassette (ABC) membrane proteins that are increasingly recognized to subserve multiple functions in human physiology. Other members of this superfamily include the drug efflux pump P-glycoprotein and the cystic fibrosis transport regulator (CFTR) [37].

The diversity of potassium channel {alpha}- and β-subunits has complicated our understanding of the relationship between individual potassium channel {alpha}-subunit genes and the currents, recognized by contemporary electrophysiologic techniques, that these gene products might transduce. Some correspondences are relatively clear (Table 1): HERG–IKr and (minK+KvLQT1)–IKs are examples. Most data now suggest that the transient outward current in the human ventricle is encoded by Kv4.3, while Kv4.2 or Kv4.2/4.3 multimers accounts for this current in other species [38,39]. One piece of evidence favoring members of the Kv4 family as encoding ITO is that when these channels are studied in heterologous expression systems, they display rapid recovery from inactivation, similar to that seen with ITO in human myocytes. However, in human endocardium, there is at least one report of a very slowly recovering transient outward current [40], raising the possibility that in select subpopulations of cells, expression of other {alpha}-subunits (e.g. Kv1.4) may also contribute to voltage-gated ion currents. This phenomenon is actually a reflection of a much larger unanswered problem, that mRNA encoding far more potassium channel subunits can be isolated from cardiac tissue than there are recognized potassium currents. One possible explanation for this apparent paradox is that individual cells or regions may express a specific repertoire of ion channel genes, different from that in the bulk of the heart. This is well-recognized at the macroscopic level (e.g. atrium vs. ventricle) and increasing evidence indicates it also occurs at the cell-to-cell level [41–44]. This possibility has obvious implications for understanding electrophysiologic remodeling. A second explanation is that expression of multiple {alpha}-subunits could contribute to an individual current. Thus, for example, voltage-independent currents (‘background’ or ‘pedestal’ currents) could reflect expression of multiple genes. A third explanation is that some mRNAs isolated from the heart are not actually present in cardiac myocytes, but rather in other tissues, such as neural or vascular elements, also located in heart. Finally, the presence of mRNA does not necessarily indicate that the mRNA is translated and the resultant functional protein inserted into the cell membrane [45].

As discussed further by Sorota in this issue, multiple chloride currents have been described in heart. One important feature of many of these currents is that they are activated or strikingly modulated by second messengers such as cAMP, PKC, elevated intracellular calcium, or stretch. The structure of chloride channel {alpha}-subunits of the ClC family are different from that of the six-membrane spanning segment motif of sodium, calcium, and potassium channels [46], although the exact organizational details of the channel proteins, or indeed how many subunits are required to generate a functional channel complex, are not yet certain. One isoform appears responsible for a volume-activated channel [47]. Most evidence points to a cardiac-specific isoform of CFTR as mediating the cAMP-activated chloride current [48,49].

Another important class of proteins for normal cardiac electrophysiology are the connexins, the structures responsible for the gap junctions that effect intercellular communication. Multiple connexin isoforms have been described in heart tissue and, as discussed further by Saffitz and colleagues in this issue, alteration in their expression or distribution within a cell may well underlie some of the perturbations in conduction velocity that so frequently occur in diseased tissue [50,51].

Regulation of intracellular ionic homeostasis requires active contributions by a range of pumps, which are often electrogenic. The most important of these are sodium–potassium ATPase and the sodium–calcium exchanger. The genes encoding the {alpha}-subunit for these structures have been cloned and there are, for example, some data to suggest that dysregulation of the sodium–calcium exchanger may contribute to (or be a response to) contractile abnormalities in congestive heart failure [52].

While ion channels, connexins, and pumps, are the most obvious candidates for regulation by a remodeling process, any consideration of the underlying mechanisms must recognize the tremendous range of other molecules that play an important role in regulating the electrophysiologic behavior of the heart. Obviously, dysregulation of their expression or function could directly or indirectly (e.g. by secondarily altering ion channel function) act as a crucial signal in the remodeling process. Examples of such molecules include structures responsible for control of intracellular calcium, elements of intracellular signaling cascades (receptors, kinases, phosphatases), or transcription factors, proteins that regulate expression of other genes. Further, it is increasingly recognized that ion channels are not expressed on the cell surface in a random fashion, but rather appear targeted to specific loci, often in association with other regulatory elements, such as kinases. The molecular basis for such subcellular targeting is now being elucidated and represents another obvious control point at which dysregulation could contribute to the remodeling process.


   3 Control of gene expression
Top
 Abstract
 1 Introduction
 2 Genes that determine...
 3 Control of gene...
4 Summary
 References
 
3.1 Transcription
Multiple processes (each one of which could be a point at which electrophysiologic remodeling could be initiated or maintained) determine the way in which the nucleotide sequence of a DNA molecule determines how an ion channel is inserted into the membrane of an excitable cell to result in an ion current. The first step in this process is gene transcription. Most DNA is tightly packed into chromatin, making it unavailable for transcription to messenger RNA (mRNA). Thus, an initial event in gene transcription is chromatin unfolding. The region of the gene immediately 5' (upstream) from the transcription start site is termed the promoter, and usually includes specific binding sites for multiple transcription factors. These proteins promote (or suppress) gene transcription as a function of external stimuli such as normal development or hormones. Most genes also include the sequence ‘TATA’ (or some close variant), known as a ‘TATA box’, immediately upstream from the transcription start site. It is the TATA box to which the enzyme RNA polymerase initially binds, and this interaction is enhanced by transcription factors.

Very little is known about the control of ion channel gene transcription. Interestingly, many members of the Kv family lack a distinct TATA box. A binding site for a cAMP-dependent transcription factor (CREB) has been identified in the Kv1.5 promoter, and cAMP has been implicated as increasing Kv1.5 transcription in heterologous systems through this mechanism [53]. Increased Kv1.5 mRNA transcripts have also been observed in heart and pituitary with glucocorticoid treatment both in vitro and in vivo [54,55] and with thyrotropin-releasing hormone in pituitary [56]. Interestingly, in the intact heart, the effect was confined to the ventricles, and was not observed in the atria [54]. While the mechanisms have not been definitely established, these hormones are known to bind with nuclear receptors to form transcriptional complexes. Specific expression in the ventricle of complexes that promote transcription is one possibility, but it is also possible that transcription is repressed in extra-ventricular tissues: tissue-specific repressor elements have been identified for the genes encoding Kv1.5 [57], neuronal sodium channels [58] and the inward rectifier Kir2.1 [59]. Perturbed transcriptional control of ion channel gene expression is one obvious potential mechanism underlying remodeling, and has been implicated in reduced ITO (Kv4.3) in heart failure [60].

Methylation of DNA suppresses transcription, and thus may be another mechanism involved in regulation of ion channel gene expression. One result of DNA methylation is the phenomenon of genomic imprinting in which expression of one parental allele is silenced. KvLQT1 localizes to a cluster of four methylated genes which in adult tissues are imprinted (the paternal allele is not expressed) [61,62]. This imprinting is actually absent in the adult heart, but in the developing mouse, the maternal KvLQT1 allele is in fact preferentially expressed [63].

3.2 RNA processing
The product of RNA polymerase is a large ‘primary’ mRNA transcript (pre-mRNA). This transcript is complementary to the DNA from which it was derived and therefore includes not only regions (exons) coding for the ultimate protein product but also regions of 5' (upstream), 3' (downstream), and intervening (intronic) sequences of non-coding DNA. This primary transcript is processed, often extensively, in the nucleus before it is translated into protein in the endoplasmic reticulum. One important process is splicing, to remove intronic (non-coding) regions and to thereby create an ‘open reading frame’ for translation into protein. Each group of three consecutive bases, termed a ‘codon’, in a given stretch of mRNA encodes a specific amino acid. Thus, translation of a given stretch of mRNA into a sequence of amino acids might result in three different proteins, depending on the starting position. The ‘start’ codon is almost inevitably AUG, which encodes methionine and the stop codon is UAG, UAA or UGA. Thus, for example, the cardiac sodium channel gene spans approximately 80 kb and includes 28 exons with 27 intervening introns [64]. Splicing removes most of the primary transcript, resulting in an mRNA of 8.4 kb. Widely-available computer programs can analyze DNA or mRNA sequences to identify ‘open reading frames’, stretches of nucleotide triplets that translate into protein without intervening stop codons. For example, the translation initiation methionine codon is located at position 150 in the sodium channel mRNA, and starts an open reading frame that is 6048 base pairs long, corresponding to a protein of 2016 amino acids [3]. The remaining ~2 kb constitute the 3'-untranslated region.

The splicing machinery recognizes specific intron–exon boundaries, and if these are disrupted (e.g. in certain long QT syndrome mutations [65,66]), a defective or truncated protein arises. It is now well-recognized that certain pre-mRNA molecules undergo a process of ‘alternative’ splicing, to result in a range of mRNA molecules whose reading frames then encode different proteins. This is the case for myosin light chains in rat skeletal muscle and for the calcitonin gene, whose alternatively spliced product (the calcitonin gene-related peptide, CGRP) may act as a neurotransmitter. More recently, both HERG and KvLQT1 have been recognized to undergo alternative splicing. At least four alternatively spliced isoforms of KvLQT1 have been recognized, but only one (isoform 1) encodes a functional ion channel protein. Isoform 2, whose mRNA has been detected in heart, has an alternatively spliced N-terminus and does not result in any functional currents when expressed alone. However, isoform 2 does appear to suppress function of isoform 1, with or without minK [33,34]. Similarly, an N-terminal splicing event in HERG results in production of two isoforms. One of these does not itself result in current but modulates function of the other and currents obtained with coexpression of the splice variants seem to recapitulate cardiac IKr gating more faithfully than does expression of the single functional mRNA [21,22]. A C-terminal alternative splicing event has also been described in HERG. Here again, expression of the alternatively spliced isoform does not result in detectable currents, but coexpression of the two splice variants results in currents with electrophysiologic properties somewhat different from those of HERG alone [23]. A tissue-specific splice variant has also been described in the C-terminus of Kv4.3 [67]. The extent to which these splicing events are tissue- or cell-specific, the mechanisms that might determine such specificity, and the way in which such alternative splicing events might be disrupted in disease to contribute to the process of remodeling are entirely open questions.

RNA editing is another interesting form of mRNA processing that may result in alternate protein products from the same pre-mRNA (or in this case the same mRNA) transcript [68]. Because mRNA is relatively unstable, a very common experimental tool is creation of a more stable DNA molecule, a cDNA, complementary to an mRNA of interest. The process of editing can be inferred when the sequences of cDNA and of genomic DNA are compared and found to be slightly different. One well-studied example with functional consequences is editing that occurs in the GluR-B subunit of the AMPA (glutamate) receptor [69]. The genomic sequence includes an adenine that is part of a codon (AAG) that encodes the amino acid glutamine at position 607, in the putative pore region. However, the corresponding cDNA sequence includes a guanine at this position (AGG), the codon for arginine. It is therefore inferred that the A in the original mRNA was edited to a G. Importantly, this single base pair editing event, that results in a change in a single amino acid, produces a profound change in the function of the expressed subunit, since glutamine-containing recombinant AMPA receptors are calcium-permeant, whereas arginine-containing receptors are calcium-impermeant. Editing is accomplished by specific mRNA editing enzymes, and variability in their expression or function is another obvious potential checkpoint for the control of cellular physiology. Indeed, AMPA receptor editing appears to occur with different efficiencies in different regions of the brain, and there has even been a suggestion that the extent of editing is altered in neurological conditions such as Alzheimer’s disease [70].

Editing of a voltage-gated ion channel has also been demonstrated [71]. When the cDNA and genomic sequences encoding the S4–S6 region of a squid Shaker-like potassium channel were compared, an astounding 17 instances of A->G editing were detected. While most of these did not result in a change in the encoded amino acid, two did, and each resulted in subtle functional changes in the encoded current. The editing process was temperature-dependent, raising the possibility that environmental cues (in this case, temperature) may provide a signal for tissue- or cell-specific editing to control cell function.

Translation of mRNA to protein generally occurs at a relatively constant rate. However, mRNA destabilization is another potential mechanism for altered ion channel expression in disease. When intracellular cAMP was increased in a glioma cell line, the abundance of mRNA encoding the K+ channel Kv1.1 was decreased, and the effect was attributed to accelerated mRNA degradation [72]. This result was accompanied by decreased Kv1.1 protein, and Kv1.1-mediated current. Along the same lines, two Kv1.4 mRNA transcripts, of 3.5 and 4.5 kilobases, with different stabilities have been identified. Translation to Kv1.4 protein in Xenopus oocytes occurs more efficiently from the 3.5 kb transcript than from the 4.5 kb one; this result has been attributed to a signal in the 3' untranslated region of the 4.5 kb transcript that is thought to decrease its stability [73].

3.3 Protein assembly and anchoring
Channel proteins are synthesized in the lumen of the rough endoplasmic reticulum, where they are inserted into lipid membrane of transport vesicles, and moved to the cell surface where membrane fusion results in insertion of the protein into the cell membrane. Given this view, the assembly of multiple {alpha} subunits that underlies normal K+ channels likely occurs prior to transport to the cell surface. Some β-subunits appear to increase expression [28], and may mediate maturation and cell surface expression of {alpha}-subunits [74,75]. Proteins also undergo a range of post-translational modifications (e.g. glycosylation) that may alter function or transport. In vitro studies suggest that ion channels may undergo rather rapid turnover, with estimated half-lives of hours in cultured cells [76]. While ion channel protein half-life in vivo is unknown, recent studies suggest connexins turn over very quickly in vivo [77]. Studies of the mechanisms whereby channel proteins are transported to and removed from the cell membrane and degraded are in their infancy.

3.4 Beat-to-beat modulation of ion channel function
While transcription and translation are ‘long term’ (hours to days) processes, channel function can also be modulated on a beat-to-beat basis. This can be accomplished by changes in the channel’s milieu (e.g. altered pHi or Ko) or by phosphorylation of channel protein, with attendant change in function. The most important acute intracellular signaling system that results in such protein phosphorylation is that related to β-adrenergic stimulation. Occupation of β1 receptors on the cell surface by agonists such as norepinephrine or isoproterenol results in a familiar cascade of intracellular events including disaggregation of heterotrimeric stimulatory G protein complexes, activation of adenylate cyclase, production of cAMP, and activation of heteromultimeric protein kinase A (PKA). Activation of this signaling pathway is well-recognized to increase ionic current through a number of channels, the best studied of which is probably the L-type calcium channel. Stimulated calcium channels undergo a ‘mode switch’ with much longer and later openings than in the non-stimulated state, but with no change in single channel conductance [78]. Presumably, phosphorylation of key residue(s) on the channel protein itself produces this functional change. Specific residues (serines or threonines) are targets for PKA-mediated phosphorylation. Similar PKA-mediated channel stimulation is also well-recognized for ICl–cAMP and IKs, and the molecular mechanisms are being worked out. Other signaling pathways that may play a crucial role in regulation of channel function include those leading to activation of protein kinase C (elevation of intracellular calcium and/or cleavage of diacylglycerol), of multi-functional calcium/calmodulin-dependent kinase (CAM kinase II) [79], and of tyrosine kinases. Kinase-induced phosphorylation is reversed by phosphatases which at least in some cases are in close physical apposition to the kinases [80]. Importantly, the signals that alter function of expressed channels on a beat-to-beat basis, also have the potential to regulate any of the more long-term processes, such as gene transcription, depicted in Fig. 1. For example, elevated intracellular calcium may not only alter channel function directly, but has also been implicated in altered expression of ion channels and other genes [81,82]. Similarly, activation of the β-adrenergic signaling pathway may exert not only important immediate effects on channel gating (presumably via direct phosphorylation of the channel protein), but may also exert important other effects on gene transcription or on mRNA stability, as outlined above.


Figure 1
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  		Fig. 1 Schematic view of mechanisms underlying ion channel expression. The specific steps underlying channel expression are indicated in the boxes, and the points at which these steps might be subject to the modulation that underlies electrophysiologic remodeling are indicated in bold. DNA transcription and mRNA processing occur in the nucleus (top). mRNA translation (to ion channels, transcription factors, or other proteins) occurs in the endoplasmic reticulum (ER), and channels are then transported to the cell surface (bottom) by vesicles secreted by the Golgi apparatus. Available evidence suggests that channels likely complex with multiple other proteins (such as anchoring elements, β-subunits, or kinases) at the cell surface.

 
It is also becoming increasingly clear that, in order for these regulatory events to occur, the kinase and the channel protein complex must be in close apposition. This physical association is brought about by anchoring proteins such as AKAP (A kinase anchoring protein) [83] and members of a superfamily, containing a specific protein binding site, termed a PDZ domain [84]. This subcellular localization of multiple protein complexes that serve to regulate each others’ function is a theme that is increasingly recognized as important in neurophysiology. One well-worked out example is in the photoreceptor system in which multiple proteins, including a seven-membrane spanning segment receptor, a calcium channel, kinases, and calmodulin, are all brought in close apposition and anchored to the actin cytoskeleton by inaD, a specific anchoring protein that includes five ‘PDZ’ binding domains [85]. Proteins that interact with the PDZ domain usually have a distinctive amino acid sequence at their C-terminus: S/TXV (serine or threonine, followed by any amino acid, followed by valine) [86]. Interestingly, both Kv1.4 and the sodium channel include a C-terminal S/TXV motif [87]. The way in which this triplet binds to the PDZ binding domain has been worked out at the crystal structure level [88]. Variations in this binding motif have also been recognized and it seems highly likely that other binding motifs which serve analogous functions to bring together channels, kinases, and other regulatory elements, will be identified. It is also likely that such binding to PDZ elements is not static. For example, phosphorylation of the C-terminus on the inward rectifier brain channel Kir2.3 prevents its interaction with PSD-95, a PDZ domain-containing protein [89].

It is intriguing that in adult myocytes, many channels appear consistently localized to the intercalated disk. This has been demonstrated for connexins [90], a subtype of ryanodine receptor, [91] the sodium channel [92], and Kv1.5 [93]. The mechanism whereby this localization occurs and its functional significance, have not been worked out. Interestingly, Kv1.5 immunostaining is not localized but, as described further by Boyden’s group in this issue, rather diffuse across the cell surface in cells that have previously undergone ischemic injury [94] and in neonatal cells [93]. Similarly, the major connexin in working myocardium (Cx43) is distributed preferentially at the ends of cells under normal conditions, but some studies have suggested that this localization is disrupted (with resultant perturbed propagation) in disease [50,51]. The mechanisms whereby ion channel and other proteins are associated with each other and the cytoskeleton are only now beginning to be understood and represent another important point at which the remodeling process may occur.


   4 Summary
Top
 Abstract
 1 Introduction
 2 Genes that determine...
 3 Control of gene...
 4 Summary
References
 
It is apparent that multiple mechanisms can underlie the tremendous diversity that is now recognized as characteristic of cardiac tissue as a function of development, of region, and of disease. Elucidating these mechanisms will prove challenging, but the fundamental processes are likely to be generalizable from those regulating gene expression and protein function in multiple other tissues. The identification of specific mechanisms underlying electrophysiologic and indeed other forms of cardiac dysregulation that lead to or accompany disease holds the obvious prospect of identifying entirely new targets for effective pharmacologic intervention to prevent and treat heart disease.

Time for primary review 21 days.


   References
Top
 Abstract
 1 Introduction
 2 Genes that determine...
 3 Control of gene...
 4 Summary
 References
 

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