Preprint Review Version 1 Preserved in Portico This version is not peer-reviewed

How Glutamate Is Managed by the Blood-Brain Barrier

Version 1 : Received: 22 September 2016 / Approved: 23 September 2016 / Online: 23 September 2016 (03:23:29 CEST)

A peer-reviewed article of this Preprint also exists.

Hawkins, R.A.; Viña, J.R. How Glutamate Is Managed by the Blood–Brain Barrier. Biology 2016, 5, 37. Hawkins, R.A.; Viña, J.R. How Glutamate Is Managed by the Blood–Brain Barrier. Biology 2016, 5, 37.


A facilitative transport system exists on the blood brain barrier (BBB) that has been tacitly assumed to be a path for glutamate entry to brain. But glutamate is a non-essential amino acid whose brain content is much greater than plasma, and studies in vivo show that glutamate does not enter brain in material quantities except in those small regions with fenestrated capillaries (circumventricular organs). The situation became understandable when luminal (blood facing) and abluminal (brain facing) membranes were isolated and studied separately. Facilitative transport of glutamate and glutamine exist only on the luminal membranes whereas Na+-dependent transport systems for glutamate, glutamine and some other amino acids are present only on the abluminal membrane. The Na+-dependent cotransporters of the abluminal membrane are in a position to actively transport amino acids from the extracellular fluid (ECF) into the endothelial cells of the BBB. These powerful secondary active transporters couple the energy of the Na+-gradient to move glutamate and glutamine into the ECF whereupon glutamate can exit to blood on the luminal facilitative glutamate transporter. Glutamine may also exit brain on a separate facilitative transport system that exists on the luminal membranes or glutamine can be hydrolyzed to glutamate within the BBB thereby releasing ammonia that is freely diffusible. The γ-glutamyl participate cycle participates indirectly by producing oxoproline (pyroglutamate) that stimulates almost all secondary active transporters yet discovered in the abluminal membranes of the BBB.


glutamate; glutamine; BBB (blood brain-barrier); brain; oxoproline; amino acid transport


Biology and Life Sciences, Anatomy and Physiology

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