Rph3a, also known as Rabphilin-3A, encodes a protein involved in multiple biological processes. It is crucial for the stabilization of the GluN2A subunit of N-methyl-D-aspartate (NMDA)-type glutamate receptors at the cell surface, forming a complex essential for synaptic plasticity and cognition [1,2]. It is also involved in processes like cell polarization in neutrophils, where it mediates the polarization of RAB21 and PIP5K1C90 important for neutrophil adhesion to endothelia [4]. In neurons, it may be associated with neuropeptide release regulation as a negative regulator of dense core vesicle (DCV) exocytosis [5].

In a study on patients with neurodevelopmental disorders, missense gain-of-function variants in Rph3A were found to increase GluN2A-containing NMDA ionotropic glutamate receptors at extrasynaptic sites, altering synaptic function and leading to a clinically variable neurodevelopmental presentation from untreatable epilepsy to autism spectrum disorder [1]. In a rat model of cerebral ischemia-reperfusion, downregulating Rph3A further worsened cerebral infarct, neuronal death, and behavioral, cognitive, and memory impairments, suggesting that the increase in Rph3A in the brain penumbra may be an endogenous protective mechanism mainly dominated by astrocytes [3].

In conclusion, Rph3a plays essential roles in synaptic function, cell polarization, and potentially in protecting against ischemia-reperfusion injury. Studies on Rph3a, including those using gene-related models like the down-regulation in the rat ischemia-reperfusion model, contribute to understanding its role in neurodevelopmental disorders and ischemic brain injury, providing insights into possible therapeutic strategies for these conditions.

References:

1. Pavinato, Lisa, Stanic, Jennifer, Barzasi, Marta, Gardoni, Fabrizio, Brusco, Alfredo. 2023. Missense variants in RPH3A cause defects in excitatory synaptic function and are associated with a clinically variable neurodevelopmental disorder. In Genetics in medicine : official journal of the American College of Medical Genetics, 25, 100922. doi:10.1016/j.gim.2023.100922. https://pubmed.ncbi.nlm.nih.gov/37403762/

2. Yang, Lei, Wei, Mengping, Wang, Yangzhen, Dong, Zhaoqi, Zhang, Chen. 2023. Rabphilin-3A undergoes phase separation to regulate GluN2A mobility and surface clustering. In Nature communications, 14, 379. doi:10.1038/s41467-023-36046-6. https://pubmed.ncbi.nlm.nih.gov/36693856/

3. Zhu, Xianlong, Li, Haiying, You, Wanchun, Wang, Zhong, Chen, Gang. 2022. Role of Rph3A in brain injury induced by experimental cerebral ischemia-reperfusion model in rats. In CNS neuroscience & therapeutics, 28, 1124-1138. doi:10.1111/cns.13850. https://pubmed.ncbi.nlm.nih.gov/35467084/

4. Ren, Chunguang, Yuan, Qianying, Jian, Xiaoying, Tang, Wenwen, Wu, Dianqing. 2020. Small GTPase ARF6 Is a Coincidence-Detection Code for RPH3A Polarization in Neutrophil Polarization. In Journal of immunology (Baltimore, Md. : 1950), 204, 1012-1021. doi:10.4049/jimmunol.1901080. https://pubmed.ncbi.nlm.nih.gov/31924649/

5. Abramian, Adlin, Hoogstraaten, Rein I, Murphy, Fiona H, Toonen, Ruud F, Verhage, Matthijs. 2024. Rabphilin-3A negatively regulates neuropeptide release, through its SNAP25 interaction. In eLife, 13, . doi:10.7554/eLife.95371. https://pubmed.ncbi.nlm.nih.gov/39412498/