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      Role of BK Potassium Channels Shaping Action Potentials and the Associated [Ca 2+] i Oscillations in GH 3 Rat Anterior Pituitary Cells

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          Measurements of electrical activity and intracellular Ca<sup>2+</sup> levels were performed in perforated-patch clamped GH<sub>3</sub> cells to determine the contribution of large-conductance calcium-activated K<sup>+</sup> (BK) channels to action potential repolarization and size of the associated Ca<sup>2+</sup> oscillations. By examining the dependence of action potential (AP) duration on extracellular Ca<sup>2+</sup> levels in the presence and the absence of the specific BK channel blocker paxilline, it is observed that plateau-like action potentials are associated to low densities of paxilline-sensitive currents. Extracellular Ca<sup>2+</sup> increases or paxilline additions are not able to largely modify action potential duration in cells showing a reduced expression of BK currents. Furthermore, specific blockade of these currents with paxilline systematically elongates AP duration, but only under conditions in which short APs and/or prominent BK currents recorded under voltage-clamp mode are present in the same cells. Our data indicate that in GH<sub>3</sub> cells, BK channels act primarily ending the action potential and suggest that by contributing to fine-tuning cellular electrical properties and hence intracellular Ca<sup>2+</sup> variations, BK channels may play an important role on time- and cell-dependent modulation of physiological outputs in adenohypophyseal cells.

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          Most cited references 21

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          Calcium--a life and death signal.

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            Calcium-activated potassium channels.

            Calcium-activated potassium channels are fundamental regulators of neuronal excitability, participating in interspike interval and spike-frequency adaptation. For large-conductance calcium-activated potassium (BK) channels, recent experiments have illuminated the fundamental biophysical mechanisms of gating, demonstrating that BK channels are voltage gated and calcium modulated. Structurally, BK channels have been shown to possess an extracellular amino-terminal domain, different from other potassium channels. Domains and residues involved in calcium-gating, and perhaps calcium binding itself, have been identified. For small- and intermediate-conductance calcium-activated potassium channels, SK and IK channels, clones have only recently become available, and they show that SK channels are a distinct subfamily of potassium channels. The biophysical properties of SK channels demonstrate that kinetic differences between apamin-sensitive and apamin-insensitive slow afterhyperpolarizations are not attributable to intrinsic gating differences between the two subtypes. Interestingly, SK and IK channels may prove effective drug targets for diseases such as myotonic muscular dystrophy and sickle cell anemia.
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              Cell-permeant caged InsP3 ester shows that Ca2+ spike frequency can optimize gene expression.

              Inositol 1,4,5-trisphosphate (InsP3) releases calcium from intracellular stores and triggers complex waves and oscillations in levels of cytosolic free calcium. To determine which longer-term responses are controlled by oscillations in InsP3 and cytosolic free calcium, it would be useful to deliver exogenous InsP3, under spatial and temporal control, into populations of unpermeabilized cells. Here we report the 15-step synthesis of a membrane-permeant, caged InsP3 derivative from myo-inositol This derivative diffused into intact cells and was hydrolysed to produce a caged, metabolically stable InsP3 derivative. This latter derivative accumulated in the cytosol at concentrations of hundreds of micromolar, without activating the InsP3 receptor. Ultraviolet illumination uncaged an InsP3 analogue nearly as potent as real InsP3, and generated spikes of cytosolic free calcium, and stimulated gene expression via the nuclear factor of activated T cells. The same total amount of InsP3 analogue elicited much more gene expression when released by repetitive flashes at 1-minute intervals than when released at 0.5- or > or = 2-minute intervals, as a single pulse, or as a slow sustained plateau. Thus, oscillations in cytosolic free calcium levels at roughly physiological rates maximize gene expression for a given amount of InsP3.

                Author and article information

                S. Karger AG
                March 2003
                03 April 2003
                : 77
                : 3
                : 162-176
                Departamento de Bioquímica y Biología Molecular, Edificio Santiago Gascón, Campus del Cristo, Universidad de Oviedo, Oviedo, Spain
                69509 Neuroendocrinology 2003;77:162–176
                © 2003 S. Karger AG, Basel

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                Page count
                Figures: 8, References: 43, Pages: 15
                Cellular Neuroendocrinology


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