TY - JOUR T1 - SIPA1L1/SPAR1 is a non-PSD protein involved in GPCR signaling JF - bioRxiv DO - 10.1101/2021.02.12.430872 SP - 2021.02.12.430872 AU - Ken Matsuura AU - Shizuka Kobayashi AU - Kohtarou Konno AU - Miwako Yamasaki AU - Takahiro Horiuchi AU - Takao Senda AU - Tomoatsu Hayashi AU - Kiyotoshi Satoh AU - Fumiko Arima-Yoshida AU - Kei Iwasaki AU - Lumi Negishi AU - Naomi Yasui-Shimizu AU - Kazuyoshi Kohu AU - Shigenori Kawahara AU - Yutaka Kirino AU - Tsutomu Nakamura AU - Masahiko Watanabe AU - Tadashi Yamamoto AU - Toshiya Manabe AU - Tetsu Akiyama Y1 - 2021/01/01 UR - http://biorxiv.org/content/early/2021/02/13/2021.02.12.430872.abstract N2 - SIPA1L1 (also known as SPAR1) has been proposed to regulate synaptic functions that are important in maintaining normal neuronal activities, such as regulating spine growth and synaptic scaling, as a component of the postsynaptic density (PSD)-95/N-methyl-D-aspartate receptor (NMDA-R)-complex. However, contrary to this view, our super-resolution and immunoelectron microscopic analyses demonstrate that SIPA1L1 is mainly localized to general submembranous and cytoplasmic regions in neurons, but scarcely to PSD. Our screening for native interactors of SIPA1L1 identified spinophilin and neurabin-1, regulators of G protein-coupled receptor (GPCR) signaling, but rejected PSD-95/NMDA-R-complex components. Furthermore, Sipa1l1-/- mice showed normal spine size distribution and NMDA-R-dependent synaptic plasticity. Nevertheless, Sipa1l1-/- mice showed aberrant responses to α2-adrenergic receptor (a spinophilin target) or adenosine A1 receptor (a neurabin-1 target) agonist stimulation and striking behavioral anomalies, such as hyperactivity, enhanced anxiety, learning impairments, social interaction deficits, and enhanced epileptic seizure susceptibility. Our findings revealed unexpected properties of SIPA1L1, suggesting a possible association of SIPA1L1 deficiency with neuropsychiatric disorders related to dysregulated GPCR signaling, such as epilepsy, attention deficit hyperactivity disorder (ADHD), autism, or fragile X syndrome.Competing Interest StatementThe authors have declared no competing interest. ER -