Differential regulation of Ca2+-activated K+ channels by beta-adrenoceptors in guinea pig urinary bladder smooth muscle.
Stimulation of beta-adrenoceptors contributes to the relaxation of urinary bladder smooth muscle (UBSM) through activation of large-conductance Ca(2+)-activated K(+) (BK) channels. We examined the mechanisms by which beta-adrenoceptor stimulation leads to an elevation of the activity of BK channels in UBSM. Depolarization from -70 to +10 mV evokes an inward L-type dihydropyridine-sensitive voltage-dependent Ca(2+) channel (VDCC) current, followed by outward steady-state and transient BK current. In the presence of ryanodine, which blocks the transient BK currents, isoproterenol, a nonselective beta-adrenoceptor agonist, increased the VDCC current by approximately 25% and the steady-state BK current by approximately 30%. In the presence of the BK channel inhibitor iberiotoxin, isoproterenol did not cause activation of the remaining steady-state K(+) current component. Decreasing Ca(2+) influx through VDCC by nifedipine or depolarization to +80 mV suppressed the isoproterenol-induced activation of the steady-state BK current. Unlike forskolin, isoproterenol did not change significantly the open probability of single BK channels in the absence of Ca(2+) sparks and with VDCC inhibited by nifedipine. Isoproterenol elevated Ca(2+) spark (local intracellular Ca(2+) release through ryanodine receptors of the sarcoplasmic reticulum) frequency and associated transient BK currents by approximately 1.4-fold. The data support the concept that in UBSM beta-adrenoceptor stimulation activates BK channels by elevating Ca(2+) influx through VDCC and by increasing Ca(2+) sparks, but not through a Ca(2+)-independent mechanism. This study reveals key regulatory molecular and cellular mechanisms of beta-adrenergic regulation of BK channels in UBSM that could provide new targets for drugs in the treatment of bladder dysfunction.
Petkov
Georgi V
GV
Department of Pharmacology, University of Vermont, College of Medicine, Given Bldg., Rm. B-331, 89 Beaumont Ave., Burlington, VT 05405-0068, USA. Georgi.Petkov@uvm.edu
Nelson
Mark T
MT
D000818:Animals; D002118:Calcium / Q000502:physiology; D006168:Guinea Pigs; D066298:In Vitro Techniques; D008297:Male; D008564:Membrane Potentials / Q000502:physiology; D009130:Muscle, Smooth / Q000502:physiology*; D024681:Potassium Channels, Calcium-Activated / Q000502:physiology*; D011943:Receptors, Adrenergic, beta / Q000502:physiology*; D015398:Signal Transduction; D001743:Urinary Bladder / Q000502:physiology*
D024681:Potassium Channels, Calcium-Activated; D011943:Receptors, Adrenergic, beta; D002118:Calcium