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Large conductance, calcium and voltage-gated potassium (BK) channels are widely distributed and essential for smooth muscle contraction, immunity, and neuronal function. PIP(2) metabolites produced by phospholipase C (PLC) that first target Ca(2+) storage, then protein kinase C, and then the BK channel are assumed to be the only way that PIP(2) regulates BK channels.

  • According to this data, PIP(2) opens BK channels without the help of PIP(2) metabolites.
  • PIP(2) modifies open and closed channel distributions and improves Ca(2+)-driven gating while having no impact on voltage gating or unitary conductance.
  • PIP(2) acyl chain length had a significant impact on how quickly channels recovered following activation; those exposed to water-soluble diC4 and diC8 recovered considerably more quickly than those exposed to PIP(2) (diC16).
  • The inositol moiety in the phospholipid headgroup, negative charge, and the RKK sequence in the S6-S7 cytosolic linker of the BK channel-forming (cbv1) subunit are all necessary for the PIP(2)-channel interaction.
  • Accessory beta(1) channel subunits significantly increase PIP(2)-induced activation, but not beta(4) channel subunits.
  • Furthermore, skeletal myocytes, whose beta(1) subunits are hardly detectable, are not affected by PIP(2powerful )'s activation of BK channels.
  • This is in contrast to vascular myocytes, where beta(1) subunits are abundantly expressed.
  • These findings show that channel accessory subunits control the final PIP(2) effect, and that this mechanism is subunit-specific.
  • Cotransfection of PI4-kinaseIIalpha and cbv1+beta(1) strongly activates BK channels in HEK293 cells, indicating a function for endogenous PIP(2) in influencing channel activity.
  • In fact, BK channel activity declines in membrane patches removed from vascular myocytes and is thereafter recovered by Mg-ATP;
  • PIP(2) antibodies added to the cytosolic membrane surface prevent this recovery.
  • Additionally, PLC inhibition combined with the blocking of downstream signaling causes a significant activation of the BK channel in intact artery myocytes under physiological settings.
  • Last but not least, pharmaceutical therapy that increases PIP(2) levels and opens BK channels widens de-endothelized arteries that control cerebral blood flow.
  • These findings suggest that endogenous PIP(2) regulates vascular tone by directly activating BK channels in vascular myocytes.

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