BACKGROUND AND PURPOSE: The large-conductance Ca(2+)-activated K(+) channel (BK(Ca), K(Ca)1.1) links membrane excitability with intracellular Ca(2+) signaling and plays important roles in smooth muscle contraction, neuronal firing, and neuroendocrine secretion. This study reports the characterization of a novel BK(Ca) channel blocker, 2,4-dimethoxy-N-naphthalen-2-yl-benzamide (A-272651). EXPERIMENTAL APPROACH: (86)Rb(+) efflux in HEK-293 cells expressing BK(Ca) was measured. Effects of A-272651 on BK(Ca) alpha- and BK(Ca) alphabeta1-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 microM) inhibited (86)Rb(+) efflux evoked by NS-1608 in HEK-293 cells expressing BK(Ca) currents. A-272651 concentration-dependently inhibited BK(Ca) currents with IC(50) values of 4.59 microM (Hill coefficient 1.04, measured at +40 mV), and 2.82 microM (Hill coefficient 0.89), respectively, for BK(Ca) alpha and BK(Ca) alphabeta1-mediated currents. Like iberiotoxin, A-272651 enhanced field stimulated twitch responses in pig detrusor and spontaneous contractions in guinea pig detrusor with EC(50) values of 4.05+/-0.05 and 37.95+/-0.12 microM, 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 BK(Ca) blockers, A-272651 represents one of the first small molecule BK(Ca) channel blockers that could serve as a useful tool for further characterization of BK(Ca) channels in physiological and pathological states.
BACKGROUND AND PURPOSE: The large-conductance Ca(2+)-activated K(+) channel (BK(Ca), K(Ca)1.1) links membrane excitability with intracellular Ca(2+) signaling and plays important roles in smooth muscle contraction, neuronal firing, and neuroendocrine secretion. This study reports the characterization of a novel BK(Ca) channel blocker, 2,4-dimethoxy-N-naphthalen-2-yl-benzamide (A-272651). EXPERIMENTAL APPROACH: (86)Rb(+) efflux in HEK-293 cells expressing BK(Ca) was measured. Effects of A-272651 on BK(Ca) alpha- and BK(Ca) alphabeta1-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 microM) inhibited (86)Rb(+) efflux evoked by NS-1608 in HEK-293 cells expressing BK(Ca) currents. A-272651 concentration-dependently inhibited BK(Ca) currents with IC(50) values of 4.59 microM (Hill coefficient 1.04, measured at +40 mV), and 2.82 microM (Hill coefficient 0.89), respectively, for BK(Ca) alpha and BK(Ca) alphabeta1-mediated currents. Like iberiotoxin, A-272651 enhanced field stimulated twitch responses in pig detrusor and spontaneous contractions in guinea pig detrusor with EC(50) values of 4.05+/-0.05 and 37.95+/-0.12 microM, 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 BK(Ca) blockers, A-272651 represents one of the first small molecule BK(Ca) channel blockers that could serve as a useful tool for further characterization of BK(Ca) channels in physiological and pathological states.
Authors: G J Christ; N S Day; M Day; C Santizo; W Zhao; T Sclafani; J Zinman; K Hsieh; K Venkateswarlu; M Valcic; A Melman Journal: Am J Physiol Regul Integr Comp Physiol Date: 2001-11 Impact factor: 3.619
Authors: Rachid El Kouhen; Carol S Surowy; Bruce R Bianchi; Torben R Neelands; Heath A McDonald; Wende Niforatos; Arthur Gomtsyan; Chih-Hung Lee; Prisca Honore; James P Sullivan; Michael F Jarvis; Connie R Faltynek Journal: J Pharmacol Exp Ther Date: 2005-04-18 Impact factor: 4.030
Authors: O B McManus; G H Harris; K M Giangiacomo; P Feigenbaum; J P Reuben; M E Addy; J F Burka; G J Kaczorowski; M L Garcia Journal: Biochemistry Date: 1993-06-22 Impact factor: 3.162
Authors: M Sausbier; H Hu; C Arntz; S Feil; S Kamm; H Adelsberger; U Sausbier; C A Sailer; R Feil; F Hofmann; M Korth; M J Shipston; H-G Knaus; D P Wolfer; C M Pedroarena; J F Storm; P Ruth Journal: Proc Natl Acad Sci U S A Date: 2004-06-11 Impact factor: 11.205
Authors: Sean C Turner; William A Carroll; Tammie K White; Murali Gopalakrishnan; Michael J Coghlan; Char-Chang Shieh; Xu-Feng Zhang; Ashutosh S Parihar; Steven A Buckner; Ivan Milicic; James P Sullivan Journal: Bioorg Med Chem Lett Date: 2003-06-16 Impact factor: 2.823
Authors: Andrea L Meredith; Kevin S Thorneloe; Matthias E Werner; Mark T Nelson; Richard W Aldrich Journal: J Biol Chem Date: 2004-06-07 Impact factor: 5.157