Gephyrin phosphorylation in the functional organization and plasticity of GABAergic synapses

Gephyrin is a multifunctional scaffold protein essential for accumulation of inhibitory glycine and GABA(A) receptors at post-synaptic sites. The molecular events involved in gephyrin-dependent GABA(A) receptor clustering are still unclear. Evidence has been recently provided that gephyrin phosphorylation plays a key role in these processes. Gephyrin post-translational modifications have been shown to influence the structural remodeling of GABAergic synapses and synaptic plasticity by acting on post synaptic scaffolding properties as well as stability. In addition, gephyrin phosphorylation and the subsequent phosphorylation-dependent recruitment of the chaperone molecule Pin1 provide a mechanism for the regulation of GABAergic signaling. Extensively characterized as pivotal enzyme controlling cell proliferation and differentiation, the prolyl-isomerase activity of Pin1 has been shown to regulate protein synthesis necessary to sustain the late phase of long-term potentiation at excitatory synapses, which suggests its involvement at synaptic sites. In this review we summarize the current state of knowledge of the signaling pathways responsible for gephyrin post translational modifications. We will also outline future lines of research that might contribute to a better understanding of molecular mechanisms by which gephyrin regulates synaptic plasticity at GABAergic synapses.