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The Journal of Neuroscience, May 1, 2001, 21(9):3135-3143

Mobilization of Calcium from Intracellular Stores, Potentiation of Neurotransmitter-Induced Calcium Transients, and Capacitative Calcium Entry by 4-Aminopyridine

Maurizio Grimaldi¹, Marco Atzori², Pulak Ray¹, and Daniel L. Alkon³

¹ Laboratory of Adaptive Systems, National Institute for Neurological Disorders and Stroke and ² National Institute of Deafness and other Communicative Disorders, National Institutes of Health, Bethesda, Maryland 20892, and ³ Blanchette Rockefeller Neurosciences Institute, Rockville, Maryland 20850

In this study we analyzed the effect of 4-aminopyridine (4-AP) on free cytosolic calcium concentration ([Ca²⁺]_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⁺]_i in type I astrocytes, neurons, and in skeletal muscle cells. The [Ca²⁺]_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⁺]_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⁺ currents in astrocytes. However, voltage-sensitive K⁺ channel blockers inhibiting these currents did not affect agonist-induced calcium transients or capacitative calcium entry, indicating that 4-AP effects on [Ca²⁺]_i were not caused by the blockade of voltage-gated K⁺ channels.

We conclude that 4-AP is able to affect calcium homeostasis at multiple levels, from increasing basal [Ca²⁺]_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.

Key words: neuron; astrocytes; muscle cell; capacitative calcium entry; intracellular calcium stores; voltage-sensitive K⁺ potassium channels

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Copyright © 2001 Society for Neuroscience  0270-6474/01/2193135-09$05.00/0

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