The gastric HAF and the isomeric NaAF (universal) are capable of regulating expression of own genes by histone phosphorylation (Ray & Chakrabarti, 1988 doi: 10.5281/zenodo.7095 and Ray, TK. 2013 10.12688/f1000research.2-165.v2) . Due to its obligatory role in cellular homeostasis it is proposed that besides gene-transcription the cellular NaAF may also be regulated by the microRNAs at the translational-level. Thus, the microRNAs are known to be responsible for regulating the essential cardiac contractile proteins (tropomyosin) acting as the “Regulator of the Regulatory protein” for muscular function. Similar to the essential role of Tropomyosin in cardiac contraction the NaAF (acting as essential regulator of homeostasis) is well-positioned to be controlled by the microRNAs at the mRNA-translation level as described below.
The expression of PMCA is reported (Brini et al. 2009, Physiol. Rev 89, 1341-78) to be transcriptionally regulated by Ca. As the PMCA is an altered form of the H, K-ATPase and Na, K-ATPase in high Ca (> 4-6 µM) environment (cut-off temporarily from NaAF-control by high Ca) to pump out the excess Ca, it is likely that the NaAF may also be transcriptionally regulated by Ca. It is noteworthy in this connection that the area-specific α-subunits (isoforms) of the Na, K-ATPase (Koksoy,AA, 2002, J. Ankara Med. School 24, 73-82; Therien & Blostein, 2000, Am. J Cell Physiol.279, C541-66) and Ca-ATPase (Jaime de Juan-Sanz et al 2014, JBC Oct 1 M114.586966; Garside et al. 2009 Neurosci. 162, 383-95) in brain tissue derived solely from α2 and α3 isoform appear indistinguishable. And numerous area specific isoforms of the Na, K-ATPase (and Ca-ATPase) in brain possibly arise from alternate splicing since95% of human genes containing multiple exons undergo alternative splicing (Wang et al. 2008 Nature 456, 470-76).
Recently, an important role for a family of regulatory RNAs has been suggested in the control of cardiac functions in health and disease (Rooiz et al. 2007 Science 316, 575-79). There are emerging evidences that microRNAs may play an important role in the pathogenesis of heart failure through their ability to regulate the expression levels of genes governing adaptive and maladaptive cardiac remodeling (Divakaran & Mann 2008 Circ. Res. 103,1072-83). Thus, besides encoding a key cardiac contractile (myofilament) regulatory-protein, the cardiac-specific microRNA, encoded by an intron of the aMHC gene, is responsible for abnormalities like cardiomyocyte hypertrophy, fibrosis, and expression of bMHC in response to stress and hypothyroidism. Thus, therapeutic manipulation of microRNAs with its target mRNA (ready to translate) could potentially increase or decrease cardiac function based on its molecular nature.
Analogous to the regulatory heart-contractile protein, tropomyosin, the universal regulator NaAF (regulating activity of the Na-pump), is also regulated up-and-down by Ca-signaling (Ray, TK 2014, RG publ. DOI: 10.13140/2.1.2737.7920). Due to the individual topmost roles played by the cardiac tropomyosin and universal NaAF, it is quite likely that similar to tropomyosin the mRNA of the self-regulating NaAF might also be regulated by specific microRNAs at the translational level.
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