Dual role of protein kinase C on BK channel regulation.

TY - JOUR

T1 - Dual role of protein kinase C on BK channel regulation.

AU - Zhou, Xiao-Bo

AU - Wulfsen, Iris

AU - Utku, Emine

AU - Sausbier, Ulrike

AU - Sausbier, Matthias

AU - Wieland, Thomas

AU - Ruth, Peter

AU - Korth, Michael

PY - 2010

Y1 - 2010

N2 - Large conductance voltage- and Ca(2+)-activated potassium channels (BK channels) are important feedback regulators in excitable cells and are potently regulated by protein kinases. The present study reveals a dual role of protein kinase C (PKC) on BK channel regulation. Phosphorylation of S(695) by PKC, located between the two regulators of K(+) conductance (RCK1/2) domains, inhibits BK channel open-state probability. This PKC-dependent inhibition depends on a preceding phosphorylation of S(1151) in the C terminus of the channel alpha-subunit. Phosphorylation of only one alpha-subunit at S(1151) and S(695) within the tetrameric pore is sufficient to inhibit BK channel activity. We further detected that protein phosphatase 1 is associated with the channel, constantly counteracting phosphorylation of S(695). PKC phosphorylation at S(1151) also influences stimulation of BK channel activity by protein kinase G (PKG) and protein kinase A (PKA). Though the S(1151)A mutant channel is activated by PKA only, the phosphorylation of S(1151) by PKC renders the channel responsive to activation by PKG but prevents activation by PKA. Phosphorylation of S(695) by PKC or introducing a phosphomimetic aspartate at this position (S(695)D) renders BK channels insensitive to the stimulatory effect of PKG or PKA. Therefore, our findings suggest a very dynamic regulation of the channel by the local PKC activity. It is shown that this complex regulation is not only effective in recombinant channels but also in native BK channels from tracheal smooth muscle.

AB - Large conductance voltage- and Ca(2+)-activated potassium channels (BK channels) are important feedback regulators in excitable cells and are potently regulated by protein kinases. The present study reveals a dual role of protein kinase C (PKC) on BK channel regulation. Phosphorylation of S(695) by PKC, located between the two regulators of K(+) conductance (RCK1/2) domains, inhibits BK channel open-state probability. This PKC-dependent inhibition depends on a preceding phosphorylation of S(1151) in the C terminus of the channel alpha-subunit. Phosphorylation of only one alpha-subunit at S(1151) and S(695) within the tetrameric pore is sufficient to inhibit BK channel activity. We further detected that protein phosphatase 1 is associated with the channel, constantly counteracting phosphorylation of S(695). PKC phosphorylation at S(1151) also influences stimulation of BK channel activity by protein kinase G (PKG) and protein kinase A (PKA). Though the S(1151)A mutant channel is activated by PKA only, the phosphorylation of S(1151) by PKC renders the channel responsive to activation by PKG but prevents activation by PKA. Phosphorylation of S(695) by PKC or introducing a phosphomimetic aspartate at this position (S(695)D) renders BK channels insensitive to the stimulatory effect of PKG or PKA. Therefore, our findings suggest a very dynamic regulation of the channel by the local PKC activity. It is shown that this complex regulation is not only effective in recombinant channels but also in native BK channels from tracheal smooth muscle.

M3 - SCORING: Zeitschriftenaufsatz

VL - 107

SP - 8005

EP - 8010

JO - P NATL ACAD SCI USA

JF - P NATL ACAD SCI USA

SN - 0027-8424

IS - 17

M1 - 17

ER -