The glycinergic and the GABAergic neurotransmission are essential inhibitory networks. Glycinergic synapses are mostly present in the spinal cord, brainstem and retina, while GABAergic synapses are preponderant in the fore-brain. Anyway, both types of receptors are often together at post-synaptic regions, thus regulating the neurotransmission at the same time but with different action mechanisms.
GABAA receptors (gamma-aminobutyric acid type A receptors) have a wide molecular complexity due to their multiple isoforms that let them modulate GABA neurotransmission in refined ways. By contrast, glycine receptors (Gly receptors) have relatively few isoforms, so that their regulation depends more on structural features, such as their number and localization, as well as on the interactions with adjacent GABAA receptors.
The features of Gly receptor are regulated by a protein called gephyrin, that binds with different affinity Gly and GABAA receptors in the post-synaptic compartment. So, gephyrin regulation modulates the activity of glycinergic synapses.
In the spinal cord neurons, gephyrin is organized in two different manners, that may be called as “cheetah” and “jaguar”. Cheetah refers to small individual gephyrin structures that are organized in small spots; these structures are typical of motoneurons. Jaguar are larger gephyrin clusters that aggregates forming jaguar-like patches on the Renshaw cells.
Cheetah spots Jaguar patches
The different organization of gephyrin reflects the function of the cells in which it is found: motoneurons have faster and less strong synapses, compared with slower and more robust synapses of Renshaw cells. Generally, Gly receptors complexes never are saturated by glycine. This property allows the speed and the continuity of neurotransmission, thus diminishing receptors saturation and desensitization.
At a molecular level, gephyrin binds to Gly receptors with high affinity. The bond is essential for increasing the number of these receptors and for localizing them in the post-synaptic region just in correspondence with the pre-synaptic sites of neurotransmitter release. In the same manner, gephyrin clusters are stabilized below the post-synaptic membrane. Instead, gephyrin bonds with GABAA receptors are weaker, thus allowing them to move to other regions of the neuron.
Gephyrin tridimensional structure is determined by alternative splicing of exons, that produces a lot of tissue- and species-specific isoforms. Moreover, gephyrin is subjected to various phosphorylation pathways that make it adopt conformations with different densities and structures. On the other hand, it has been observed a reduction of gephyrin clusters size when they are submitted to dephosphorylation, but few is known about these mechanisms yet.
Building and degradation control of gephyrin clusters is complex and little known so far. Cytoskeleton actin filaments could have a major role, for example because filaments depolymerization reduces the size of gephyrin clusters, and vice versa. Less gephyrin also means a major mobility of Gly receptors, that can leave the post-synaptic surface or just move to other sites in order to set up a new structural organization.
More proteins are involved in this process. For example, neuroligin-2 and -4 have a role in the recruitment of gephyrin and in the stabilization of the whole synapsis. Also, neuroligin activates collybistin, a protein that binds gephyrin in all inhibitory synapses, whose role seems to be essential especially in GABAergic synapses, even though further studies will be needed to better explain its function.
When there are Gly and GABAA receptors at the same time in the same post-synaptic place, we talk about “mixed” synapses. Mixed synapsis are typical of growing neurons, then they disappear after post-synaptic neuron maturation, being replaced by just one type of receptor. Anyway, some adult cells in spinal cord, like Renshaw cells, maintain the mixed structure, while motoneurons downregulate GABAA receptors. A possible explication is that Gly receptors have a fast inhibitory response (6 ms), while GABAA receptors reacts more slowly (15 – 20 ms). So, some cells might control the strength and the time of inhibition using the different properties of both receptors.
Gephyrin is a key protein in the regulation of inhibitory synapses. It controls post-synaptic structures, receptors retention, number, density and ratios of both Gly and GABAA receptors. It is controlled by a number of kinases and phosphatases, as well as by other proteins and cytoskeleton actin filaments.
Alvarez F.J. Gephyrin and the regulation of synaptic strength and dynamics atglycinergic inhibitory synapses. Brain Res Bull. 2016 Sep 6. pii: S0361-9230(16)30238-6.
The elaboration of this post has been financed by the project PI15/01082, as a part of the National Plan of I+D+I and co-financed by the ISCIII – General Deputy Direction for Evaluation and Development of Health Research – and the European Regional Development Fund (ERDF).