Collybistin SH3 ‐protein isoforms are expressed in the rat brain promoting gephyrin and GABA‐A receptor clustering at GABAergic synapses

ARHGEF9 encodes several collybistin splice variants which can be grouped into ones that possess the auto ‐inhibitory SH3 domain (CBSH3+) and ones that do not (CBSH3−), the latter being constitutively active. CBSH3+ and CBSH3− bind to gephyrin forming the GABAergic postsynaptic scaffold. The predominant CBSH3+ isoform has been extensively studied but not CBSH3−, whose function has been largely o verlooked. We are now showing that CBSH3− variants play a significant role in regulating the size of the postsynaptic GABAergic scaffold. AbstractCollybistin (CB) is a guanine nucleotide exchange factor (GEF) selectively localized at GABAergic and glycinergic postsynapses. Analysis of mRNA shows that several isoforms of collybistin are expressed in the brain. Some of the isoforms have a SH3 domain (CBSH3+) and some have no SH3 domain (CBSH3 −). The CBSH3+ mRNAs are predominantly expressed over CBSH3−. However, in an immunoblot study of mouse brain homogenates, only CBSH3+ protein isoforms were detected, proposing that CBSH3− protein might not be expressed in the brain. The expression or lack of expression of CBSH3− protein is a n important issue because CBSH3− has a strong effect in promoting the postsynaptic clustering of gephyrin and GABA‐A receptors (GABAARs). Moreover CBSH3 − is constitutively active; therefore lower expression of CBSH3− protein might play a relatively stronger functional role than the more abundant but self‐inhibited CBSH3+ isoforms, wh...

Source: Journal of Neurochemistry - January 5, 2021 Category: Neuroscience Authors: Shanu George, John Bear, Michael J. Taylor, Karthik Kanamalla, Christopher D. Fekete, Tzu ‐Ting Chiou, Celia P. Miralles, Theofilos Papadopoulos, Angel L. De Blas Tags: ORIGINAL ARTICLE Source Type: research