Work

Phosphoinositide‐ and Collybistin‐Dependent Synaptic Clustering of Gephyrin

Year: 2025

Type: article

Abstract: receptors. At specific GABAergic synapses, the nucleotide exchange factor collybistin recruits gephyrin to the postsynaptic membrane via interaction with phosphoinositides. However, the molecular mechanisms underlying the formation, maintenance, and regulation of collybistin-dependent gephyrin clusters remain poorly understood. This study sheds light on the molecular mechanism of gephyrin cluster formation on the basis of gephyrin self-oligomerization induced by collybistin, leading to the formation of a high-molecular weight (> 5 MDa) gephyrin-collybistin complex, which is regulated in two ways: First, plasma-membrane phosphoinositides promote complex formation, demonstrating their critical role in membrane targeting and stabilization of gephyrin-collybistin clusters at postsynaptic sites. Second, gephyrin phosphorylation at Ser325 abolishes complex formation with collybistin, thus impairing collybistin-dependent gephyrin clustering at GABAergic synapses. Collectively, our data demonstrate a molecular mechanism for synaptic clustering of gephyrin, which involves collybistin- and phosphoinositide-dependent formation of high-molecular weight gephyrin oligomers.

Source: Journal of Neurochemistry

DOI: 10.1111/jnc.70169