Mobilization of calcium from intracellular stores, potentiation of neurotransmitter-induced calcium transients, and capacitative calcium entry by 4-aminopyridine
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abstract
In this study we analyzed the effect of 4-aminopyridine (4-AP) on free cytosolic calcium concentration ([Ca2%2b]i) in basal conditions, after stimulation with neurotransmitters, and during capacitative calcium entry. Using fura-2 ratiometric calcium imaging, we found that 4-AP increased [Ca2%2b]i in type I astrocytes, neurons, and in skeletal muscle cells. The [Ca2%2b]i elevation induced by 4-AP was concentration-dependent and consisted of two phases: the first was dependent on intracellular calcium mobilization, and the second was dependent on extracellular calcium influx. 4-AP also increased the second messenger inositol trisphosphate in both neurons and astrocytes. In astrocytes, 4-AP treatment potentiated the sustained phase of the [Ca2%2b]i elevation induced by ATP and bradykinin. In addition, capacitative calcium entry was potentiated severalfold by 4-AP, in astrocytes and muscle cells but not in neurons. These effects of 4-AP were completely and promptly reversible. 4-AP blocked voltage-sensitive K%2b currents in astrocytes. However, voltage-sensitive K%2b channel blockers inhibiting these currents did not affect agonist-induced calcium transients or capacitative calcium entry, indicating that 4-AP effects on [Ca2%2b]i were not caused by the blockade of voltage-gated K %2b channels. We conclude that 4-AP is able to affect calcium homeostasis at multiple levels, from increasing basal [Ca2%2b]i to potentiating capacitative calcium entry. The potentiation of capacitative calcium entry in astrocytes or muscle cells may explain some of the therapeutic activities of 4-AP as a neurotransmission enhancer.
