Study on the Role of KV7 Channels in Regulating Smooth Muscle Contraction in Mouse Corpus Cavernosum

Academic Background

Erectile dysfunction (ED) is a significant health issue that impacts the quality of life for men. Since the introduction of phosphodiesterase 5 (PDE5) inhibitors like Sildenafil in the 1990s, there has been notable progress in the treatment of ED. However, a considerable number of patients do not respond to PDE5 inhibitors, especially those with chronic conditions such as diabetes, where the efficacy is more limited. Therefore, finding new therapeutic targets has become a focal point of current research. The contraction and relaxation of corpus cavernosum smooth muscle (CCSM) are key regulatory factors in erectile function, and potassium ion channels (Kv channels) play an important role in regulating the membrane potential and calcium ion (Ca²⁺) signals of smooth muscle. Among them, the Kv7 channel family (encoded by KCNQ genes) regulates membrane potential and cellular excitability in various tissues, but its role in the corpus cavernosum has not been fully elucidated.

The aim of this study was to explore the regulatory role of Kv7 channels in Ca²⁺ signaling and smooth muscle contraction in mouse corpus cavernosum, with the hope of providing new insights for the treatment of ED.

Source of the Paper

This study was conducted by Mitchell Mercer, Mark A. Hollywood, Gerard P. Sergeant, and Keith D. Thornbury from the Smooth Muscle Research Center at Dundalk Institute of Technology, Ireland. The paper was first published on January 20, 2025, in the journal American Journal of Physiology-Cell Physiology, with the DOI: 10.1152/ajpcell.00980.2024.

Research Process

1. Gene Expression Detection of Kv7 Channels

The researchers first detected the transcriptional expression of KCNQ1-5 genes in mouse corpus cavernosum tissue using quantitative PCR (qPCR). The results showed that KCNQ1, KCNQ3-5 genes were expressed in the corpus cavernosum tissue, with KCNQ5 having the highest expression level, while KCNQ2 was not detected. Additionally, immunocytochemical experiments confirmed the expression of Kv7.5 protein in isolated corpus cavernosum smooth muscle cells.

2. Effects of Kv7 Channel Modulators on Corpus Cavernosum Contraction

Through in vitro experiments, the researchers observed the effects of Kv7 channel modulators on spontaneous contractions and phenylephrine (PE)-induced contractions in the corpus cavernosum. The results showed: - The Kv7 channel opener Retigabine (RTG) could inhibit spontaneous contractions and contractions induced by low concentrations of PE (0.3 μM). - The Kv7 channel blocker XE-991 enhanced these contractions. - The L-type Ca²⁺ channel blocker Nifedipine completely inhibited these contractions, indicating their dependence on Ca²⁺ influx.

3. Effects of Kv7 Channel Modulators on Ca²⁺ Signals

Using single-cell Ca²⁺ imaging technology, the researchers observed the effects of Kv7 channel modulators on Ca²⁺ waves in corpus cavernosum smooth muscle cells. The results showed: - RTG inhibited spontaneous Ca²⁺ waves and Ca²⁺ waves induced by low concentrations of PE (0.1 μM), but had no significant effect on Ca²⁺ waves induced by high concentrations of PE (10 μM). - XE-991 enhanced these Ca²⁺ waves.

4. Role of Kv7 Channels in PE Concentration Effects

The researchers further explored the role of Kv7 channels in contractions induced by different concentrations of PE (0.1-30 μM). The results showed: - Low concentrations of PE mainly induced phasic contractions, while high concentrations of PE mainly induced tonic contractions. - RTG only inhibited phasic contractions and had no significant effect on tonic contractions, indicating that phasic contractions depend on membrane potential, whereas tonic contractions do not.

Main Results

1. Expression of Kv7 Channels: KCNQ1, KCNQ3-5 genes are expressed in corpus cavernosum tissue, and Kv7.5 protein is expressed in smooth muscle cells.
2. Effects of Kv7 Channel Modulators on Contraction: RTG inhibits spontaneous contractions and contractions induced by low concentrations of PE, XE-991 enhances these contractions, and Nifedipine completely inhibits these contractions.
3. Effects of Kv7 Channel Modulators on Ca²⁺ Signals: RTG inhibits spontaneous Ca²⁺ waves and Ca²⁺ waves induced by low concentrations of PE, XE-991 enhances these Ca²⁺ waves.
4. Role of Kv7 Channels in PE Concentration Effects: RTG only inhibits phasic contractions and has no significant effect on tonic contractions.

Conclusion

This study found that Kv7 channels (especially Kv7.5) are functionally expressed in mouse corpus cavernosum smooth muscle and participate in regulating membrane potential and Ca²⁺ signals. The Kv7 channel opener RTG can inhibit phasic contractions and Ca²⁺ waves induced by low concentrations of PE but has no significant effect on tonic contractions induced by high concentrations of PE. This suggests that Kv7 channels may become a new target for treating ED, especially for patients who do not respond to PDE5 inhibitors.

Research Highlights

1. Important Findings: Functional expression of Kv7 channels in corpus cavernosum smooth muscle and their regulatory effects on contractions and Ca²⁺ signals.
2. Significance of the Study: Provides new potential targets for the treatment of ED, especially for patients who do not respond to PDE5 inhibitors.
3. Methodological Innovation: Combining qPCR, immunocytochemistry, in vitro contraction experiments, and single-cell Ca²⁺ imaging techniques to comprehensively reveal the mechanism of action of Kv7 channels.

Application Value

This study provides a theoretical basis for developing new ED treatment drugs targeting Kv7 channels, especially for patients with chronic diseases such as diabetes. Future research can further explore the expression and functional changes of Kv7 channels under different pathological conditions to support personalized treatment.