Gephyrin
Gephyrin is a multifunctional protein primarily known for its critical role in the postsynaptic clustering of glycine receptors (GlyRs) and some subtypes of GABAA receptors at inhibitory synapses in the central nervous system.
Function
Gephyrin acts as a scaffolding protein, anchoring and organizing these inhibitory neurotransmitter receptors at the postsynaptic membrane. It does so through direct binding interactions with specific receptor subunits. In addition to its role in receptor clustering, gephyrin is also involved in the biosynthesis of molybdenum cofactor (MoCo), a crucial component for several enzymes, including sulfite oxidase, xanthine oxidase, and aldehyde oxidase. This MoCo biosynthesis function is considered to be a more ancestral role, predating its synaptic functions.
Structure
Gephyrin is composed of several distinct domains, each with specialized functions. Key domains include the G-domain (involved in oligomerization), the C-domain (involved in receptor binding), and the N-terminal domain. The oligomerization of gephyrin is crucial for its scaffolding function, allowing it to form a lattice-like structure that stabilizes the postsynaptic receptor cluster.
Clinical Significance
Mutations in the GPHN gene, which encodes gephyrin, are associated with a variety of neurological disorders, including hyperekplexia (startle disease), epilepsy, and intellectual disability. These disorders often arise from impaired inhibitory neurotransmission due to the disruption of gephyrin's receptor clustering function. Deficiencies in MoCo biosynthesis, also linked to GPHN mutations, can lead to severe neurological dysfunction and even death.
Expression
Gephyrin is widely expressed throughout the central nervous system, particularly in regions rich in inhibitory synapses, such as the spinal cord, brainstem, and hippocampus. Its expression levels are developmentally regulated, reflecting the changing needs of the developing nervous system.
Interactions
Gephyrin interacts with a diverse array of proteins, including GlyRs, GABAA receptors, tubulin, and components of the cytoskeleton. These interactions are critical for its scaffolding function and for regulating the dynamics of inhibitory synapses.