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RPTPmu and protein tyrosine phosphorylation regulate K(+) channel mRNA expression in adult cardiac myocytes
1Department of Pharmacology, University of Pittsburgh, Pittsburgh, Pennsylvania 15261, USA.
Abstract:
Previously, we reported that cell-cell contact regulates K(+) channel mRNA expression in cultured adult rat cardiac myocytes. Here we show that exposing cardiac myocytes to tyrosine kinase inhibitors (genistein, tyrphostin A25), but not inactive analogs, prevents downregulation of Kv1.5 mRNA and upregulation of Kv4.2 mRNA normally observed when they are cultured under low-density conditions. Furthermore, cardiac myocytes cocultured with cells that endogenously (Mv 1 Lu) or heterologously (Chinese hamster ovary cells) express the receptor-type protein tyrosine phosphatase mu (RPTPmu) display Kv1.5 mRNA levels paralleling that which was observed in myocytes cultured under high-density conditions and in intact tissue. In contrast, myocytes cocultured with control cells failed to produce this response. Finally, it is shown that Kv4.2 mRNA expression is unaffected by RPTPmu. These findings reveal that multiple tyrosine phosphorylation-dependent mechanisms control cardiac myocyte K(+) channel genes. Furthermore, we conclude that RPTPmu specifically regulates cardiac myocyte Kv1.5 mRNA expression. Thus this receptor protein tyrosine phosphatase may be important in responses to pathological conditions associated with the loss of cell-cell interactions in the heart.
Insights
Cell-cell contact influences cardiac potassium channel gene expression. Receptor-type protein tyrosine phosphatase mu (RPTPmu) specifically regulates Kv1.5 mRNA, impacting heart conditions.
Area of Science:
- Cardiovascular Biology
- Molecular Cardiology
- Ion Channel Physiology
Background:
- Cell-cell contact is known to regulate potassium channel mRNA expression in cardiac myocytes.
- Understanding these regulatory mechanisms is crucial for cardiac health and disease.
Purpose of the Study:
- To investigate the role of tyrosine phosphorylation in regulating cardiac myocyte potassium channel gene expression.
- To identify specific signaling pathways involved in cell-cell contact-mediated gene regulation.
Main Methods:
- Treatment of cultured adult rat cardiac myocytes with tyrosine kinase inhibitors (genistein, tyrphostin A25).
- Coculture of cardiac myocytes with cells expressing receptor-type protein tyrosine phosphatase mu (RPTPmu) or control cells.
- Quantitative analysis of Kv1.5 and Kv4.2 mRNA expression levels.
Main Results:
- Tyrosine kinase inhibitors prevented the downregulation of Kv1.5 mRNA and upregulation of Kv4.2 mRNA under low-density conditions.
- Coculture with RPTPmu-expressing cells normalized Kv1.5 mRNA levels, mimicking high-density culture conditions.
- Kv4.2 mRNA expression was not affected by RPTPmu.
Conclusions:
- Multiple tyrosine phosphorylation-dependent pathways regulate cardiac myocyte potassium channel genes.
- Receptor-type protein tyrosine phosphatase mu (RPTPmu) specifically controls Kv1.5 mRNA expression.
- RPTPmu may play a significant role in cardiac responses to the loss of cell-cell interactions.