collybistin

Collybistin is a brain-enriched guanine nucleotide exchange factor (GEF) for the small GTPase Cdc42, encoded by the ARHGEF9 gene on the X chromosome. It belongs to the Dbl homology (DH)–pleckstrin homology (PH) family of RhoGEFs and, in some isoforms, contains an SH3 domain. The DH–PH module catalyzes the exchange of GDP for GTP on Cdc42, while the PH domain supports membrane association, helping position the catalytic activity at postsynaptic membranes.

In neurons, collybistin acts as an organizer of inhibitory GABAergic synapses. It interacts with gephyrin, a major postsynaptic scaffolding protein, promoting gephyrin clustering and the accumulation of GABA_A receptors at inhibitory synapses. This collaboration is important for the maturation and maintenance of inhibitory synapses and for proper GABAergic neurotransmission.

Genetic disruption of ARHGEF9 or loss of collybistin function leads to defects in gephyrin clustering and reduced synaptic labeling of GABA_A receptors, resulting in impaired inhibitory synaptic transmission. In humans, pathogenic variants in ARHGEF9 are associated with X-linked intellectual disability and epilepsy, occasionally accompanied by cortical malformations or hypotonia. Animal models with reduced collybistin function exhibit diminished inhibitory synapses and increased seizure susceptibility, supporting its role in stabilizing inhibitory networks.

Collybistin thus serves as a critical molecular link between cytoskeletal dynamics and inhibitory synapse organization, contributing to the balance of excitatory and inhibitory signaling essential for normal brain function.