Large-conductance voltage- and Ca -activated K channel regulation by protein kinase C in guinea pig urinary bladder smooth muscle

نویسندگان

  • Kiril L. Hristov
  • Amy C. Smith
  • Shankar P. Parajuli
  • John Malysz
  • Georgi V. Petkov
چکیده

Hristov KL, Smith AC, Parajuli SP, Malysz J, Petkov GV. Large-conductance voltageand Ca -activated K channel regulation by protein kinase C in guinea pig urinary bladder smooth muscle. Am J Physiol Cell Physiol 306: C460–C470, 2014. First published December 18, 2013; doi:10.1152/ajpcell.00325.2013.—Large-conductance voltageand Ca -activated K (BK) channels are critical regulators of detrusor smooth muscle (DSM) excitability and contractility. PKC modulates the contraction of DSM and BK channel activity in nonDSM cells; however, the cellular mechanism regulating the PKC-BK channel interaction in DSM remains unknown. We provide a novel mechanistic insight into BK channel regulation by PKC in DSM. We used patch-clamp electrophysiology, live-cell Ca imaging, and functional studies of DSM contractility to elucidate BK channel regulation by PKC at cellular and tissue levels. Voltage-clamp experiments showed that pharmacological activation of PKC with PMA inhibited the spontaneous transient BK currents in native freshly isolated guinea pig DSM cells. Current-clamp recordings revealed that PMA significantly depolarized DSM membrane potential and inhibited the spontaneous transient hyperpolarizations in DSM cells. The PMA inhibitory effects on DSM membrane potential were completely abolished by the selective BK channel inhibitor paxilline. Activation of PKC with PMA did not affect the amplitude of the voltage-stepinduced whole cell steady-state BK current or the single BK channel open probability (recorded in cell-attached mode) upon inhibition of all major Ca sources for BK channel activation with thapsigargin, ryanodine, and nifedipine. PKC activation with PMA elevated intracellular Ca levels in DSM cells and increased spontaneous phasic and nerve-evoked contractions of DSM isolated strips. Our results support the concept that PKC activation leads to a reduction of BK channel activity in DSM via a Ca -dependent mechanism, thus increasing DSM contractility.

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تاریخ انتشار 2014