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This Article Full Text Full Text (PDF) All Versions of this Article: 90/6/3828    most recent 00617.2003v1 Alert me when this article is cited Alert me if a correction is posted Citation Map Services Email this article to a friend Similar articles in this journal Similar articles in Web of Science Similar articles in PubMed Alert me to new issues of the journal Download to citation manager Citing Articles Citing Articles via HighWire Citing Articles via Web of Science (5) Citing Articles via Google Scholar Google Scholar Articles by Xie, Z. Articles by Fox, A. P. Search for Related Content PubMed PubMed Citation Articles by Xie, Z. Articles by Fox, A. P.

Role of Cl^– Co-Transporters in the Excitation Produced by GABA_A Receptors in Juvenile Bovine Adrenal Chromaffin Cells

¹ Department of Anesthesia and Critical Care, The University of Chicago, Chicago, Illinois 60637 ³ Departments of Neurobiology, Pharmacology and Physiology, The University of Chicago, Chicago, Illinois 60637 ² Department of Anesthesiology and Pharmacology, Vanderbilt University, Nashville, Tennessee 37232-2520

Submitted 27 June 2003; accepted in final form 25 August 2003

GABA is the primary inhibitory neurotransmitter in the adult mammalian brain. However, in neonatal animals, activation of Cl^–-permeable GABA receptors is excitatory and appears to depend on the expression of a Na⁺-K⁺-2Cl^– cotransporter (NKCC) that elevates intracellular Cl^– levels, leading to a depolarized Cl^– equilibrium potential (E_Cl). The change from excitation to inhibition appears to involve the expression of the K⁺/Cl^– co-transporter, KCC2, which lowers intracellular Cl^– levels resulting in a hyperpolarized E_Cl. In this study, we show that bovine chromaffin cells from 4- to 5-mo-old animals are excited by GABA. Activation of GABA_A receptors depolarizes the cells, opens voltage-dependent Ca²⁺ channels, elevates [Ca²⁺]_i, and promotes the release of catecholamines. Blockade of voltage-dependent Ca²⁺ channels prevents the elevation of [Ca²⁺]_i by GABA. The extrapolated anion reversal potential in these cells is approximately –28 mV, indicating a resting intracellular anion concentration of approximately 50 mM. Expression of KCC2 protein was not detected in the juvenile chromaffin cells. In contrast, clear expression of NKCC1 was observed. Blockade of NKCC1 should reduce the intracellular Cl^– concentration and hyperpolarize E_Cl. Bumetanide, an NKCC1 blocker, reduced the elevation of [Ca²⁺]_i by GABA. In some cells, activation of GABA_A receptors inhibits responses to excitatory neurotransmitters, even though GABA itself is depolarizing. Co-activation of cholinergic and GABA_A receptors in chromaffin cells produced elevations in [Ca²⁺]_i that were comparable to those produced by cholinergic receptors alone. Our data showing the selective expression of chloride co-transporters and the resulting strongly depolarized anion reversal potential may help explain how activation of GABA_A receptors causes sufficient excitation to elicit catecholamine release from chromaffin cells.

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