GABAA Receptor and Glycine Receptor Activation by Paracrine/Autocrine Release of Endogenous Agonists: More Than a Simple Communication Pathway

Abstract

It is a common and widely accepted assumption that glycine and GABA are the main inhibitory transmitters in the central nervous system (CNS). But, in the past 20 years, several studies have clearly demonstrated that these amino acids can also be excitatory in the immature central nervous system. In addition, it is now established that both GABA receptors (GABARs) and glycine receptors (GlyRs) can be located extrasynaptically and can be activated by paracrine release of endogenous agonists, such as GABA, glycine, and taurine. Recently, non-synaptic release of GABA, glycine, and taurine gained further attention with increasing evidence suggesting a developmental role of these neurotransmitters in neuronal network formation before and during synaptogenesis. This review summarizes recent knowledge about the non-synaptic activation of GABA(A)Rs and GlyRs, both in developing and adult CNS. We first present studies that reveal the functional specialization of both non-synaptic GABA(A)Rs and GlyRs and we discuss the neuronal versus non-neuronal origin of the paracrine release of GABA(A)R and GlyR agonists. We then discuss the proposed non-synaptic release mechanisms and/or pathways for GABA, glycine, and taurine. Finally, we summarize recent data about the various roles of non-synaptic GABAergic and glycinergic systems during the development of neuronal networks and in the adult.

Selective transport of neurotransmitters and modulators by distinct volume-regulated LRRC8 anion channels

“…In addition to being an important osmolyte, the sulfo-amino acid taurine activates inhibitory glycine and, possibly, γ-aminobutyric acid (GABA) receptors (Le-Corronc et al, 2011;Schmieden et al, 1989). It might also serve as a gliotransmitter in central osmoregulation (Choe et al, 2012;Hussy et al, 2000Hussy et al, , 1997Le-Corronc et al, 2011).…”

“…It might also serve as a gliotransmitter in central osmoregulation (Choe et al, 2012;Hussy et al, 2000Hussy et al, , 1997Le-Corronc et al, 2011). Glutamate [and to a lesser degree aspartate (Chen et al, 2005;Patneau and Mayer, 1990)] activates excitatory glutamate receptors, with swelling-induced release of glutamate thought to play a role in pathological conditions such as stroke and spreading depression (Akita and Okada, 2014).…”

Non-Neuronal Release of Gamma-Aminobutyric Acid by Embryonic Pluripotent Stem Cells

“…Both ES and ECS cells expressed a1, a2, a3, a4, a5, b2, p, and r1 GABA A receptor subunits. Despite minor variability in the expression patterns of receptor subunits among different studies [10,11,15], expression of the a1, a3, a4, and a5 subunits, which are orthosteric sites for GABA binding [16], was found in these studies and by our group. Receptors containing subunits a4 and a5 predominantly accumulate in extrasynaptic sites [17,18].…”

“…Receptors containing subunits a4 and a5 predominantly accumulate in extrasynaptic sites [17,18]. The functional properties of these extrasynaptic GABA A receptors are different from those of the postsynaptic receptors, which permits these receptors to respond to slow autocrine or paracrine release [16]. Thus, they are also expressed in synapse-free progenitors in the brain and are responsible for cell proliferation, differentiation, and migration [16].…”

“…Two isoforms, GAD67 and GAD65, have been identified. The former is constitutively active, whereas the latter oscillates between an active holoenzyme and an inactive apoenzyme [16]. In neurons, GAD67 and GAD65 are involved in the synthesis of cytoplasmic and the vesicular pools of GABA, respectively [20].…”