The Journal of Neurophysiology Vol. 80 No. 3 September 1998, pp. 1105-1115
Copyright ©1998 The American Physiological Society

Calcium Released From Intracellular Stores Inhibits GABA_A-Mediated Currents in Ganglion Cells of the Turtle Retina

Abram Akopian¹, Robert Gabriel^{1, 3}, and Paul Witkovsky^{1, 2}

¹ Department of Ophthalmology and ² Department of Physiology and Neuroscience, New York University School of Medicine, New York, New York 10016; and ³ Department of General Zoology and Neurobiology, Janus Pannonius University, H-7604 Pecs, Hungary

Akopian, Abram, Robert Gabriel, and Paul Witkovsky. Calcium released from intracellular stores inhibits GABA_A-mediated currents in ganglion cells of the turtle retina. J. Neurophysiol. 80: 1105-1115, 1998. We studied spiking neurons isolated from turtle retina by the whole cell version of the patch clamp. The studied cells had perikaryal diameters >15 µm and fired multiple spikes in response to depolarizing current steps, indicating they were ganglion cells. In symmetrical [Cl], currents elicited by puffs of 100 µM -aminobutyric acid (GABA) were inward at a holding potential of -80 mV. All of the GABA-evoked current was blocked by SR95331 (20 µM), indicating that it was mediated by a GABA_A receptor. The GABA-evoked currents were unaltered by eliciting a transmembrane calcium current either just before or during the response to GABA. On the other hand caffeine (10 mM), which induces Ca²⁺ release from intracellular stores, inhibited the GABA-evoked current on average by 30%. The caffeine effect was blocked by introducing the calcium buffer bis-(o-aminophenoxy)-N,N,N',N'-tetraacetic acid (BAPTA) into the cell but was unaffected by replacing [Ca²⁺]_o with equimolar cobalt. Thapsigargin (10 µM), an inhibitor of intracellular calcium pumps, and ryanodine (20 µM), which depletes intracellular calcium stores, both markedly reduced a caffeine-induced inhibition of the GABA-evoked current. Another activator of intracellular calcium release, inositol trisphosphate (IP₃; 50 µM), also progressively reduced the GABA-induced current when introduced into the cell. Dibutyryl adenosine 3',5'-cyclic monophosphate (cAMP; 0.5 mM), a membrane-permeable analogue of cAMP, did not reduce GABA-evoked currents, suggesting that cAMP-dependent kinases are not involved in suppressing GABA_A currents, whereas calmidazolium (30 µM) and cyclosporin A(20 µM), which inhibit Ca/calmodulin-dependent phosphatases, did reduce the caffeine-induced inhibition of the GABA-evoked current. Alkaline phosphatase (150 µg/ml) and calcineurin (300 µg/ml) had a similar action to caffeine or IP₃. Antibodies directed against the ryanodine receptor or the IP₃ receptor reacted with the great majority of neurons in the ganglion cell layer. We found that these two antibodies colocalized in large ganglion cells. In summary, intracellular calcium plays a role in reducing the currents elicited by GABA, acting through GABA_A receptors. The modulatory action of calcium on GABA responses appears to work through one or more Ca-dependent phosphatases.

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