Characterization and functional roles of Kv7 Channels in corpus cavernosum smooth muscle
Lee, SW1; Chae, MR1; Kang, SJ1; Han, DH1; Sung, HH1; Chung, JD1; Choi, CI1; Choi, YH1; Choi, BR2; Park, JK2
1: Samsung Medical Center, Sungkyunkwan University School of Medicine, Seoul, Korea, South; 2: Chonbuk National University School of Medicine, Jeonju, Korea, South
Objectives: KCNQ-encoded voltage-gated potassium channels (Kv7) have recently been identified as key regulator of vascular and non-vascular smooth muscle tone. Kv7 channel subtypes (Kv7.1-Kv7.5) have a specific tissue distribution and pathophysiological role. Loss of function mutations in four of the five KV7 genes lead to distinct inherited diseases, such as cardiac arrhythmias, epilepsy and sensorineuronal deafness. However, their physiological role in corporal smooth muscle (CSM) remains to be fully elucidated. In this study, we examined the molecular expression and functional role of Kv7 channels in corporal smooth muscle.
Materials & Methods: Expression of KCNQ isoforms in human corporal smooth muscle (hCSM) cells was examined using RT-PCR. Functional responses to Kv7 channel modulators were evaluated in normal and diabetic (DM) rabbit corporal smooth muscle (CSM) tissue. Isolated CSM strips were mounted in an organ-bath system, and the relaxation effects of the following Kv7 channel subtype selective activators: ML213 (Kv7.2/Kv7.4channels), ML277 (Kv7.1) and ICA 069673 (Kv7.2/7.3), Flupirtine (Kv7.2–7.5 channels) were evaluated by cumulative addition to strips pre-contracted with10-5 M phenylephrine (PE). Fluo-4 fluorescence techniques were used to monitor changes in [Ca2+]cyt.
Results: Of the five KCNQ subtypes, the transcripts for KCNQ1, KCNQ3-KCNQ5 were detected in human corpus cavernosum smooth muscle cells. In functional studies, Flupirtine, ML277 and ML213 produced a concentration-dependent relaxation of PE-induced contractions, with potencies of ML213> Flupirtine> ML277 (at 30 µM, ML213: 100.9±7.7%, Flupirtine: 59.4±14.3%, ML277: 29.1±1.8%, n=8, p<0.05). Whereas ICA 069673 was effective at 100 µM (42.3±8.2% at 100 µM, n=8, p<0.05). The effects of ML213 was attenuated by pre-incubation with 1 µM XE991 (Kv7.1–7.5 channel blocker) (n=8, p<0.05), which in turn confirmed Kv7 channels selectivity. Moreover, ML213 also induced concentration-dependent relaxation in CSM strips from diabetic rabbit, with similar potency in normal rabbit. XE991 (10 µM) induced a significant increase in [Ca2+]cyt in cultured hCSMs (n=8, p<0.05)
Conclusions: These data suggest that Kv7channels, most probably Kv7.4 channels play a role in erectile function and might be a novel therapeutic target for treatment of erectile dysfunction.
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