Postnatal development of transmural gradients in expression of ion channels and Ca2+-handling proteins in the ventricle

Transmural gradients in ion channel and auxiliary subunit expression

“…Furthermore, despite pharmacological and kinetic properties that resemble the Kv1.4 channel, the transient outward current in the rabbit atrium was inhibited by antisense oligonucleotides directed against Kv4.2 and Kv4.3, with the Kv4.3 antisense oligos having a larger inhibitory effect than Kv1.4 antisense oligos (Wang et al, 1999). Expression of Kv1.4 mRNA in the rabbit ventricle during development does not parallel the marked postnatal increase in I to , whereas expression of all three I to,f subunit genes does match this increase (Abd Allah et al, 2012; Sanchez-Chapula et al, 1994). Similarly, the downregulation of I to observed in rabbit ventricular myocytes in heart failure is paralleled by a decrease in expression of the Kv4.2 and KChIP2 proteins, while Kv1.4 protein levels remain unchanged (Rose et al, 2005).…”

“…Although transmural gradients can, in principle, be generated by many different mechanisms, including transcriptional, post-transcriptional or post-translational regulation as well as modulation by signaling pathways, transcriptional regulation appears to play the major role in determining regional differences in ion current expression patterns. Several large-scale ion channel gene expression surveys in the heart have shown a generally good correlation between gene expression levels and current expression for most of the channels and transporters analyzed (Abd Allah et al, 2012; Chandler et al, 2009; Gaborit et al, 2007; Soltysinska et al, 2009; Szentadrassy et al, 2005). …”

“…The Kv1.4 gene is expressed in the rabbit ventricles and atria, but so are the I to,f subunit genes, Kv4.2, Kv4.3 as well as the KChIP2 auxiliary subunit. In adult ventricle, these genes are expressed at comparable levels to Kv1.4 (Abd Allah et al, 2012; Rose et al, 2005); Rosati and McKinnon unpublished results). Furthermore, despite pharmacological and kinetic properties that resemble the Kv1.4 channel, the transient outward current in the rabbit atrium was inhibited by antisense oligonucleotides directed against Kv4.2 and Kv4.3, with the Kv4.3 antisense oligos having a larger inhibitory effect than Kv1.4 antisense oligos (Wang et al, 1999).…”

“…Although the early ontogenesis of the ventricular wall appears to provide the initial basis for the establishment of transmural gradients in channel and transporter gene expression in heart, the gradients observed in the adult are generally established during postnatal development (Abd Allah et al, 2012). Multiple transcription factors are differentially expressed across the ventricular wall in adult heart, in keeping with the hypothesis that different, developmentally determined, gene regulatory programs are in place in these myocytes (Costantini et al, 2005; Rosati et al, 2006).…”

“…Evolution of a given gene’s promoter and of the various cis-regulatory modules that modulate the function of that promoter is known, more specifically, as cis-regulatory evolution. Baseline expression of ion channels in heart appears to be predominantly determined at the level of transcription (Abd Allah et al, 2012; Chandler et al, 2009; Gaborit et al, 2007; Marionneau et al, 2005; Rosati and McKinnon, 2004). Consequently, it is likely that cis-regulatory evolution will be a major factor determining tissue specific channel expression levels in the heart and there is experimental evidence to support this hypothesis (Yan et al, 2012).…”