Opinion
Protein kinases: tuners of the BKCa channel in smooth muscle

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Abstract

Large-conductance, Ca2+-activated K+ (BKCa) channels in smooth muscle cells are unique because they integrate changes in both intracellular Ca2+ and membrane potential. Protein kinases such as cAMP-dependent protein kinase, cGMP-dependent protein kinase and protein kinase C can affect tissue function by ‘tuning’ the apparent Ca2+- and/or voltage-sensitivity of the BKCa channel to physiological changes in both Ca2+ concentrations and membrane potential. However, despite the central importance of kinase-mediated modulation of BKCa channels in different smooth muscle tissues, many key issues, including the sites and mechanisms of actions of protein kinases, remain unresolved. In this article, the role of protein kinases in the regulation of BKCa channels is discussed.

Section snippets

PKA

The first protein kinase shown to affect the activity of smooth muscle BKCa channels was PKA (Fig. 1a) and several studies have confirmed this effect (Table 1). An alteration of BKCa channel activity was observed with either PKA concentrations between 10 and 500 nm or PKA activities between 0.01 and 50.00 U ml−1 (activities between 5 and 20 U ml−1 have been used most often). The EC50 for the PKA-induced activation of porcine tracheal BKCa channels is 0.12 U ml−1 (Ref. 17). By contrast, neither

Phosphorylation modulates BKCa channel activity

Although indirect mechanisms have been proposed 18, it is likely that the effects of protein kinases on BKCa channels involve direct phosphorylation of the channel protein. Several lines of evidence support this hypothesis.

Direct and indirect activation of BKCa channels by protein kinases

Another important issue is how protein kinases interact with the BKCa channel. There are two alternative hypotheses. The first suggests that protein kinases interact directly with the channel protein, whereas the second suggests that protein kinases interact with the channel indirectly, via other protein(s). It should be emphasized that this discussion is limited to data obtained from isolated BKCa channels, where factors that are known to affect BKCa channel function in intact cells, such as Ca

Concluding remarks

The activity of smooth muscle BKCa channels is regulated by protein kinases (Fig. 4). In most cases PKA and PKG stimulate and PKC inhibits channel activity by shifting the voltage–activation curve without changing single-channel conductance or voltage-sensitivity. This effect occurs following phosphorylation, which could be either direct at the channel, or indirect via a phosphatase. Questions regarding the interaction of different kinases at the BKCa channel, the effect of the kinases on

Chemical name

KT5823(9S,10R,12R)-2,3,9,10,11,12-hexahydro-10-methoxy-2,9-dimethyl-1-oxo-9,12-epoxy-1H-diindolo[1,2,3-fg:3′,2′,1′-Kl]pyrrolo[3,4-i][1,6]benzo-diazocine-10-carboxylic acid, methyl ester

Acknowledgements

This work was supported by grants from Deutsche Forschungsgemeinschaft and the NIH. We would like to thank A. Bonev, T. Heppner and G. Perez for critical reading of the manuscript.

References (67)

  • T.J. Heppner

    Ca2+-activated K+ channels regulate action potential repolarization in urinary bladder smooth muscle

    Am. J. Physiol. Cell Physiol.

    (1997)
  • J.E. Brayden et al.

    Regulation of arterial tone by activation of calcium-dependent potassium channels

    Science

    (1992)
  • V. Berczi

    Pressure-induced activation of membrane K+ current in rat saphenous artery

    Hypertension

    (1992)
  • C.D. Benham et al.

    Spontaneous transient outward currents in single visceral and vascular smooth muscle cells of the rabbit

    J. Physiol.

    (1986)
  • M.T. Nelson

    Relaxation of arterial smooth muscle by calcium sparks

    Science

    (1995)
  • J.H. Jaggar

    Calcium sparks in smooth muscle

    Am. J. Physiol. Cell Physiol.

    (2000)
  • M.T. Nelson et al.

    Physiological roles and properties of potassium channels in arterial smooth muscle

    Am. J. Physiol. Cell Physiol.

    (1995)
  • H. Miyoshi et al.

    Calcitonin gene-related peptide activates the K+ channels of vascular smooth muscle cells via adenylate cyclase

    Basic Res. Cardiol.

    (1995)
  • Y.M. Song et al.

    β-Adrenoceptor stimulation activates large-conductance Ca2+- activated K+ channels in smooth muscle cells from basilar artery of guinea pig

    Pflügers Arch.

    (1995)
  • W. Peng

    Regulation of Ca2+-activated K+ channels in pulmonary vascular smooth muscle cells – role of nitric oxide

    J. Appl. Physiol.

    (1996)
  • G.O. Carrier

    Nitrovasodilators relax mesenteric microvessels by cGMP-induced stimulation of Ca-activated K channels

    Am. J. Physiol. Heart Circ. Physiol.

    (1997)
  • L. Toro

    Maxi-KCa, a unique member of the voltage-gated K channel superfamily

    News Physiol. Sci.

    (1998)
  • R. Brenner

    Vasoregulation by the β1 subunit of the calcium-activated potassium channel

    Nature

    (2000)
  • H. Kume

    β-Adrenergic agonists regulate KCa channels in airway smooth muscle by cAMP-dependent and -independent mechanisms

    J. Clin. Invest.

    (1994)
  • R.E. White

    cAMP-dependent vasodilators cross-activate the cGMP-dependent protein kinase to stimulate BKCa channel activity in coronary artery smooth muscle cells

    Circ. Res.

    (2000)
  • X.B. Zhou

    BK(Ca) channel activation by membrane-associated cGMP kinase may contribute to uterine quiescence in pregnancy

    Am. J. Physiol. Cell Physiol.

    (2000)
  • U. Klockner et al.

    ATP suppresses activity of Ca2+-activated K+ channels by Ca2+ chelation

    Pflügers Arch.

    (1992)
  • M.Y. Lee

    Modulation of large conductance calcium-activated K+ channel by membrane-delimited protein kinase and phosphatase activities

    Pflügers Arch.

    (1994)
  • Z.W. Wang et al.

    Activation of KCa channels in airway smooth muscle cells by endogenous protein kinase A

    Am. J. Physiol. Lung Cell. Mol. Physiol.

    (1996)
  • D.L. Williams

    Guanosine 5′-monophosphate modulates gating of high-conductance Ca2+-activated K+ channels in vascular smooth muscle cells

    Proc. Natl. Acad. Sci. U. S. A.

    (1988)
  • K. Fujino

    Effects of nitroglycerin on ATP-induced Ca+-mobilization, Ca+-activated K channels and contraction of cultured smooth muscle cells of porcine coronary artery

    J. Pharmacol. Exp. Ther.

    (1991)
  • A. Alioua

    PKG-I α phosphorylates the α-subunit and upregulates reconstituted GKCa channels from tracheal smooth muscle

    Am. J. Physiol. Lung Cell. Mol. Physiol.

    (1995)
  • M. Nara

    Guanylyl cyclase stimulatory coupling to KCa channels

    Am. J. Physiol. Cell Physiol.

    (2000)
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