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

Georgi Petkov, Mark T. Nelson

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62 Citations (Scopus)

Abstract

Stimulation of β-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 β-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 β-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 m V 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 β-adrenoceptor stimulation activates BK channels by elevating Ca2+ influx through VDCC and by increasing Ca2+ sparks, but not through a Ca 2+-independent mechanism. This study reveals key regulatory molecular and cellular mechanisms of β-adrenergic regulation of BK channels in UBSM that could provide new targets for drugs in the treatment of bladder dysfunction.

Original languageEnglish (US)
JournalAmerican Journal of Physiology - Cell Physiology
Volume288
Issue number6 57-6
DOIs
StatePublished - Jun 1 2005
Externally publishedYes

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Large-Conductance Calcium-Activated Potassium Channels
Calcium-Activated Potassium Channels
Adrenergic Receptors
Smooth Muscle
Muscle
Isoproterenol
Guinea Pigs
Urinary Bladder
Electric sparks
Electric potential
Chemical activation
Depolarization
Nifedipine
Ryanodine
Ryanodine Receptor Calcium Release Channel
Sarcoplasmic Reticulum
Colforsin
Adrenergic Agents
Pharmaceutical Preparations

All Science Journal Classification (ASJC) codes

  • Clinical Biochemistry
  • Cell Biology
  • Physiology

Cite this

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title = "Differential regulation of Ca2+-activated K+ channels by β-adrenoceptors in guinea pig urinary bladder smooth muscle",
abstract = "Stimulation of β-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 β-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 β-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 m V 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 β-adrenoceptor stimulation activates BK channels by elevating Ca2+ influx through VDCC and by increasing Ca2+ sparks, but not through a Ca 2+-independent mechanism. This study reveals key regulatory molecular and cellular mechanisms of β-adrenergic regulation of BK channels in UBSM that could provide new targets for drugs in the treatment of bladder dysfunction.",
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AU - Nelson, Mark T.

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N2 - Stimulation of β-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 β-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 β-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 m V 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 β-adrenoceptor stimulation activates BK channels by elevating Ca2+ influx through VDCC and by increasing Ca2+ sparks, but not through a Ca 2+-independent mechanism. This study reveals key regulatory molecular and cellular mechanisms of β-adrenergic regulation of BK channels in UBSM that could provide new targets for drugs in the treatment of bladder dysfunction.

AB - Stimulation of β-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 β-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 β-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 m V 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 β-adrenoceptor stimulation activates BK channels by elevating Ca2+ influx through VDCC and by increasing Ca2+ sparks, but not through a Ca 2+-independent mechanism. This study reveals key regulatory molecular and cellular mechanisms of β-adrenergic regulation of BK channels in UBSM that could provide new targets for drugs in the treatment of bladder dysfunction.

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