Mechanisms Underlying Heterogeneous Ca 2+ Sparklet Activity in Arterial Smooth Muscle

  • Navedo M
  • Amberg G
  • Nieves M
  • et al.
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Abstract

In arterial smooth muscle, single or small clusters of Ca 2+ channels operate in a high probability mode, creating sites of nearly continual Ca 2+ influx (called “persistent Ca 2+ sparklet” sites). Persistent Ca 2+ sparklet activity varies regionally within any given cell. At present, the molecular identity of the Ca 2+ channels underlying Ca 2+ sparklets and the mechanisms that give rise to their spatial heterogeneity remain unclear. Here, we used total internal reflection fluorescence (TIRF) microscopy to directly investigate these issues. We found that tsA-201 cells expressing L-type Cavα1.2 channels recapitulated the general features of Ca 2+ sparklets in cerebral arterial myocytes, including amplitude of quantal event, voltage dependencies, gating modalities, and pharmacology. Furthermore, PKCα activity was required for basal persistent Ca 2+ sparklet activity in arterial myocytes and tsA-201 cells. In arterial myocytes, inhibition of protein phosphatase 2A (PP2A) and 2B (PP2B; calcineurin) increased Ca 2+ influx by evoking new persistent Ca 2+ sparklet sites and by increasing the activity of previously active sites. The actions of PP2A and PP2B inhibition on Ca 2+ sparklets required PKC activity, indicating that these phosphatases opposed PKC-mediated phosphorylation. Together, these data unequivocally demonstrate that persistent Ca 2+ sparklet activity is a fundamental property of L-type Ca 2+ channels when associated with PKC. Our findings support a novel model in which the gating modality of L-type Ca 2+ channels vary regionally within a cell depending on the relative activities of nearby PKCα, PP2A, and PP2B.

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Navedo, M. F., Amberg, G. C., Nieves, M., Molkentin, J. D., & Santana, L. F. (2006). Mechanisms Underlying Heterogeneous Ca 2+ Sparklet Activity in Arterial Smooth Muscle . The Journal of General Physiology, 127(6), 611–622. https://doi.org/10.1085/jgp.200609519

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