BK channel regulation by phosphodiesterase type 1

A novel signaling pathway controlling human detrusor smooth muscle function

Wenkuan Xin, Ning Li, Vitor S. Fernandes, Biao Chen, Eric S. Rovner, Georgi Petkov

Research output: Contribution to journalArticle

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Abstract

Large-conductance Ca2+-activated K+ (BK) channels are critical regulators of detrusor smooth muscle (DSM) function. We aimed to investigate phosphodiesterase type 1 (PDE1) interactions with BK channels in human DSM to determine the mechanism by which PDE1 regulates human urinary bladder physiology. A combined electrophysiological, functional, and pharmacological approach was applied using human DSM specimens obtained from open bladder surgeries. The perforated whole cell patch-clamp technique was used to record transient BK currents (TBKCs) and the cell membrane potential in freshly isolated human DSM cells in combination with the selective PDE1 inhibitor, 8-methoxymethyl-3-isobutyl-1-methylxanthine (8MM-IBMX). Isometric DSM tension recordings were used to measure spontaneous phasic and electrical field stimulation-induced contractions in human DSM isolated strips. Selective pharmacological inhibition of PDE1 with 8MM-IBMX (10 μM) increased TBKC activity in human DSM cells, which was abolished by subsequent inhibition of protein kinase A (PKA) with H-89 (10 μM). The stimulatory effect of 8MM-IBMX on TBKCs was reversed upon activation of muscarinic acetylcholine receptors with carbachol (1 μM). 8MM-IBMX (10 μM) hyperpolarized the DSM cell membrane potential, an effect blocked by PKA inhibition. 8MM-IBMX significantly decreased spontaneous phasic and nerve-evoked contractions of human DSM isolated strips. The results reveal a novel mechanism that pharmacological inhibition of PDE1 attenuates human DSM excitability and contractility by activating BK channels via a PKA-dependent mechanism. The data also suggest interactions between PDE1 and muscarinic signaling pathways in human DSM. Inhibition of PDE1 can be a novel therapeutic approach for the treatment of overactive bladder associated with detrusor overactivity.

Original languageEnglish (US)
Pages (from-to)F994-F999
JournalAmerican Journal of Physiology - Renal Physiology
Volume310
Issue number10
DOIs
StatePublished - May 15 2016

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Large-Conductance Calcium-Activated Potassium Channels
Phosphoric Diester Hydrolases
Smooth Muscle
Cyclic AMP-Dependent Protein Kinases
Smooth Muscle Myocytes
Pharmacology
Membrane Potentials
Urinary Tract Physiological Phenomena
Urinary Bladder
Cell Membrane
Calcium-Activated Potassium Channels
Overactive Urinary Bladder
Muscle Tonus
Phosphodiesterase Inhibitors
Carbachol
Patch-Clamp Techniques
Muscarinic Receptors
Human Activities
Cholinergic Agents
Electric Stimulation

All Science Journal Classification (ASJC) codes

  • Physiology
  • Urology

Cite this

BK channel regulation by phosphodiesterase type 1 : A novel signaling pathway controlling human detrusor smooth muscle function. / Xin, Wenkuan; Li, Ning; Fernandes, Vitor S.; Chen, Biao; Rovner, Eric S.; Petkov, Georgi.

In: American Journal of Physiology - Renal Physiology, Vol. 310, No. 10, 15.05.2016, p. F994-F999.

Research output: Contribution to journalArticle

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