Characterization and functional roles of KCNQ-encoded voltage-gated potassium (Kv7) channels in human corpus cavernosum smooth muscle

• Published in: Pflügers Archiv Vol. 472; no. 1; pp. 89 - 102
• Main Authors: Lee, Jun Ho, Chae, Mee Ree, Kang, Su Jeong, Sung, Hyun Hwan, Han, Deok Hyun, So, Insuk, Park, Jong Kwan, Lee, Sung Won
• Format: Journal Article
• Language: English
• Published: Berlin/Heidelberg Springer Berlin Heidelberg 2020; Springer Nature B.V
• Subjects: Anilides - pharmacology; Animals; Anthracenes - pharmacology; Biomedical and Life Sciences; Biomedicine; Bridged Bicyclo Compounds - pharmacology; Calcium (intracellular); Cell Biology; Cell membranes; Cells, Cultured; Cyclic AMP-Dependent Protein Kinases - antagonists & inhibitors; Diabetes mellitus; Diabetes Mellitus, Experimental - metabolism; Endothelium; Enzyme inhibitors; Erectile dysfunction; Human Physiology; Humans; Hydrazones - pharmacology; Ion Channels; Isoquinolines - pharmacology; Isoxazoles - pharmacology; KCNQ1 protein; KCNQ4 protein; Kinases; Male; Membrane potential; Molecular Medicine; Muscle Contraction; Muscle Relaxation; Muscle, Smooth - cytology; Muscle, Smooth - metabolism; Muscle, Smooth - physiology; Myocytes, Smooth Muscle - metabolism; Myocytes, Smooth Muscle - physiology; Neurosciences; Penis - cytology; Potassium; Potassium Channel Blockers - pharmacology; Potassium channels; Potassium channels (voltage-gated); Potassium Channels, Voltage-Gated - antagonists & inhibitors; Potassium Channels, Voltage-Gated - metabolism; Protein kinase A; Protein kinase A inhibitors; Protein Kinase Inhibitors - pharmacology; Rabbits; Rats; Receptors; Receptors and Transporters; Smooth muscle; Sulfonamides - pharmacology; KCNQ; Corpus cavernosum; Erectile dysfunction; Kv7.4 channel; KCNE
• ISSN: 0031-6768; 1432-2013
• DOI: 10.1007/s00424-019-02343-7

The group of KCNQ-encoded voltage-gated potassium (Kv7) channels includes five family members (Kv7.1–7.5). We examined the molecular expression and functional roles of Kv7 channels in corporal smooth muscle (CSM). Isolated rabbit CSM strips were mounted in an organ bath system to characterize Kv7 channels during CSM relaxation. Intracellular Ca
2+
levels were measured in the CSM using the Ca
2+
dye Fluo-4 AM. The expression of the KCNQ1–5 (the encoding genes for Kv7.1–7.5) and KCNE1–5 subtypes was determined by quantitative real-time PCR. Electrophysiological recordings and an in situ proximity ligation assay (PLA) were also performed. ML213 (a Kv7.2/7.4/7.5 activator) exhibited the most potent relaxation effect. XE911 (a Kv7.1–7.5 blocker) significantly inhibited the relaxation caused by ML213. Removal of the endothelium from the CSM did not affect the relaxation effect of ML213. H-89 (a protein kinase A inhibitor) and ESI-09 (an exchange protein directly activated by cAMP inhibitor) significantly inhibited ML213-induced relaxation (H-89: 31.3%; ESI-09: 52.7%). XE991 significantly increased basal [Ca
2+
]
i
in hCSM cells. KCNQ4 (the Kv7.4-encoding gene) and KCNE4 in CSM were the most abundantly expressed subtypes in humans and rats, respectively. KCNQ4 and KCNE4 expression was significantly decreased in diabetes mellitus rats. ML213 significantly increased the outward current amplitude. XE991 inhibited the ML213-induced outward currents. ML213 hyperpolarized the hCSM cell membrane potential. Subsequent addition of XE991 completely reversed the ML213-induced hyperpolarizing effects. A combination of Kv7.4 and Kv7.5 antibodies generated a strong PLA signal. We found that the Kv7.4 channel is a potential target for ED treatment.