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- Title
A-272651, a nonpeptidic blocker of large-conductance Ca2+-activated K+ channels, modulates bladder smooth muscle contractility and neuronal action potentials.
- Authors
Shieh, C.-C.; Turner, S. C.; Zhang, X.-F.; Milicic, I.; Parihar, A.; Jinkerson, T.; Wilkins, J.; Buckner, S. A.; Gopalakrishnan, M.
- Abstract
Background and Purpose:The large-conductance Ca2+-activated K+ channel (BKCa, KCa1.1) links membrane excitability with intracellular Ca2+ signaling and plays important roles in smooth muscle contraction, neuronal firing, and neuroendocrine secretion. This study reports the characterization of a novel BKCa channel blocker, 2,4-dimethoxy-N-naphthalen-2-yl-benzamide (A-272651).Experimental Approach:86Rb+ efflux in HEK-293 cells expressing BKCa was measured. Effects of A-272651 on BKCa α- and BKCa αβ1-mediated currents were evaluated by patch-clamp. Effects on contractility were assessed using low-frequency electrical field stimulated pig detrusor and spontaneously contracting guinea pig detrusor. Effects of A-272651 on neuronal activity were determined in rat small diameter dorsal root ganglia (DRG).Key Results:A-272651 (10 μM) inhibited 86Rb+ efflux evoked by NS-1608 in HEK-293 cells expressing BKCa currents. A-272651 concentration-dependently inhibited BKCa currents with IC50 values of 4.59 μM (Hill coefficient 1.04, measured at +40 mV), and 2.82 μM (Hill coefficient 0.89), respectively, for BKCa α and BKCa αβ1-mediated currents. Like iberiotoxin, A-272651 enhanced field stimulated twitch responses in pig detrusor and spontaneous contractions in guinea pig detrusor with EC50 values of 4.05±0.05 and 37.95±0.12 μM, respectively. In capsaicin-sensitive DRG neurons, application of A-272651 increased action potential firing and prolonged action potential duration.Conclusions and Implications:These data demonstrate that A-272651 modulates smooth muscle contractility and neuronal firing properties. Unlike previously reported peptide BKCa blockers, A-272651 represents one of the first small molecule BKCa channel blockers that could serve as a useful tool for further characterization of BKCa channels in physiological and pathological states.British Journal of Pharmacology (2007) 151, 798–806; doi:10.1038/sj.bjp.0707278; published online 21 May 2007
- Subjects
NAPHTHALENE; BENZAMIDE; POTASSIUM channels; CALCIUM; BLADDER; BIOLOGICAL membranes; SMOOTH muscle; SENSORY neurons; BLADDER innervation; ACTION potentials; ANIMAL experimentation; DOSE-effect relationship in pharmacology; ELECTROPHYSIOLOGY; SENSORY ganglia; GUINEA pigs; HYDROCARBONS; MEMBRANE proteins; MOLECULAR structure; MUSCLE contraction; NEURONS; PEPTIDES; RADIOISOTOPES in medical diagnosis; RATS; SWINE; IN vitro studies; CHEMICAL inhibitors
- Publication
British Journal of Pharmacology, 2007, Vol 151, Issue 6, p798
- ISSN
0007-1188
- Publication type
journal article
- DOI
10.1038/sj.bjp.0707278