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MEMBRANE TRANSPORTERS, ION CHANNELS, AND PUMPS

Differential regulation of Ca²⁺-activated K⁺ channels by -adrenoceptors in guinea pig urinary bladder smooth muscle

Department of Pharmacology, The University of Vermont, College of Medicine, Burlington, Vermont

Submitted 5 August 2004 ; accepted in final form 19 January 2005

Stimulation of -adrenoceptors contributes to the relaxation of urinary bladder smooth muscle (UBSM) through activation of large-conductance Ca²⁺-activated K⁺ (BK) channels. We examined the mechanisms by which -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 Ca²⁺ 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 -adrenoceptor agonist, increased the VDCC current by 25% and the steady-state BK current by 30%. In the presence of the BK channel inhibitor iberiotoxin, isoproterenol did not cause activation of the remaining steady-state K⁺ current component. Decreasing Ca²⁺ 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 Ca²⁺ sparks and with VDCC inhibited by nifedipine. Isoproterenol elevated Ca²⁺ spark (local intracellular Ca²⁺ release through ryanodine receptors of the sarcoplasmic reticulum) frequency and associated transient BK currents by 1.4-fold. The data support the concept that in UBSM -adrenoceptor stimulation activates BK channels by elevating Ca²⁺ influx through VDCC and by increasing Ca²⁺ sparks, but not through a Ca²⁺-independent mechanism. This study reveals key regulatory molecular and cellular mechanisms of -adrenergic regulation of BK channels in UBSM that could provide new targets for drugs in the treatment of bladder dysfunction.

Ca²⁺ sparks; voltage-dependent Ca²⁺ channel; ryanodine receptor