IQSEC2, also known as BRAG1, is a guanine nucleotide exchange factor (GEF) highly enriched in synapses. It is bound to N-methyl-D-aspartate (NMDA)-type glutamate receptors via PSD-95. Activation of NMDA receptors leads to calcium-calmodulin binding to IQSEC2's IQ domain, causing a conformational change that activates the SEC7 catalytic domain. This results in GTP-GDP exchange on ARF6, which promotes downregulation of surface AMPA-type glutamate receptors through a JNK-mediated pathway. IQSEC2 is crucial for neuronal development and synaptic plasticity [1,3].

Experiments using IQSEC2 transgenic and knockout (KO) mouse models have recapitulated autistic-like behavior and epileptic seizures in affected animals. In KO mice, IQSEC2 is involved in both inhibitory and stimulatory neurotransmission. Mutated or absent IQSEC2 arrests neuronal development, leading to immature neuronal networks with subsequent aberrant maturation, increased inhibition, and reduced neuronal transmission. The levels of Arf6-GTP remain constitutively high in KO mice despite the absence of IQSEC2 protein, indicating impaired regulation of the Arf6 guanine nucleotide exchange cycle [2].

In conclusion, IQSEC2 is essential for normal neuronal development and synaptic function. IQSEC2 KO mouse models have been instrumental in revealing its role in conditions such as autism and epilepsy, highlighting its significance in understanding these neurodevelopmental and neurological disorders.

References:

1. Levy, Nina S, Umanah, George K E, Rogers, Eli J, Lache, Orit, Levy, Andrew P. 2019. IQSEC2-Associated Intellectual Disability and Autism. In International journal of molecular sciences, 20, . doi:10.3390/ijms20123038. https://pubmed.ncbi.nlm.nih.gov/31234416/

2. Levy, Nina S, Borisov, Veronika, Lache, Orit, Levy, Andrew P. 2023. Molecular Insights into IQSEC2 Disease. In International journal of molecular sciences, 24, . doi:10.3390/ijms24054984. https://pubmed.ncbi.nlm.nih.gov/36902414/

3. Petersen, Amber, Brown, Joshua C, Gerges, Nashaat Z. 2018. BRAG1/IQSEC2 as a regulator of small GTPase-dependent trafficking. In Small GTPases, 11, 1-7. doi:10.1080/21541248.2017.1361898. https://pubmed.ncbi.nlm.nih.gov/29363391/