Blockade of Kv7 channels reverses the inhibitory effects of exchange protein directly activated by cAMP activation on purinergic contractions of the murine detrusor

• Published in: Basic & clinical pharmacology & toxicology Vol. 133; no. 1; pp. 29 - 42
• Main Authors: Fong, Zhihui, Lall, Anshika, Mullins, Nicolas D., Santana, L. Fernando, Hollywood, Mark A., Thornbury, Keith D., Sergeant, Gerard P.
• Format: Journal Article
• Language: English
• Published: England Wiley Subscription Services, Inc 01-07-2023
• Subjects: bladder and urethra pharmacology; Ca2+-transporting ATPase; Calcium ions; Channels; Cyclic AMP; Electric fields; ion channels as drug targets; Modulators; Myocytes; Nifedipine; potassium channels; Potassium channels (calcium-gated); Potassium channels (voltage-gated); Protein kinase A; Purine P2X receptors; urinary incontinence; ion channels as drug targets; bladder and urethra pharmacology; urinary incontinence; potassium channels
• ISSN: 1742-7835; 1742-7843
• DOI: 10.1111/bcpt.13881

Purinergic contractions of the detrusor are reduced by cAMP, but the underlying mechanisms are unclear. We examined the effects of BK and Kv7 channel modulators on purinergic contractions of the detrusor and tested if the inhibitory effects of activators of the cAMP effectors, PKA and EPAC, were reduced by blockade of BK or Kv7 channels. Purinergic contractions of the murine detrusor were induced by electric field stimulation (EFS) or application of the P2X receptor agonist α,β‐MeATP. EFS responses were inhibited by the L‐type Ca2+ channel blocker nifedipine, but not by the SERCA inhibitor CPA or the SOCE blocker GSK7975A. The Kv7 channel opener retigabine and BK channel activator compound X inhibited purinergic responses, while blockade of Kv7 or BK channels with XE991 or iberiotoxin, respectively, augmented these responses. Application of the EPAC activator 007‐AM or PKA activator 6‐MB‐cAMP inhibited EFS responses. These effects were unaffected by iberiotoxin; however, XE991 reduced the effects of 007‐AM, but not 6‐MB‐cAMP. Kv7.5 was the only Kv7 transcript detected in isolated detrusor myocytes. These data suggest that purinergic contractions of the detrusor are regulated by BK and Kv7 channels and the latter may also play a role in EPAC‐dependent inhibition of this activity.