Neuronal transmembrane chloride electrochemical gradient: A key player in GABAA receptor activation physiological effect

Summary.  It has long been accepted that GABA is the main inhibitory neurotransmitter in the mammalian brain, acting via GABA_A or GABA_B receptors. However, new evidences have shown that it may work as an excitatory transmitter, especially in the brain of newly-born animals and acting via GABA_A receptors. The difference in the end results of GABA_A receptors activation in the two cases is not due to the receptor associated channels, which in both cases are chloride channels. The different physiological effect in the two cases is due to different electrochemical gradients for chloride. When GABA acting via GABA_A receptors is inhibitory, either there is no transmembrane electrochemical gradient for chloride or there is one forcing such negative ions into the nerve cell, once chloride channels are open. Viceversa, GABA is excitatory when the electrochemical gradient is such to make chloride ions flow outside the cell, upon opening of the GABA activated chloride channels. In this review this concept is discussed in details and evidence in the scientific literature for the existence of different types of chloride pumps (either internalizing or extruding chloride) is compiled. Received August 5, 2002 Accepted October 30, 2002 Published online March 17, 2003 Acknowledgement The author thanks Dr. Simona Scarrone, Genova, for helping him with the schemes in Fig. 1. Author's address: Dr. Aroldo Cupello, Istituto di Bioimmagini e Fisiologia Molecolare, Via De Toni 5, I-16132 Genova, Italy, Fax: 39-010354180, E-mail: dcupel@neurologia.unige.it