The ubiquitin-like protein Plic-1 enhances the membrane insertion of GABAA receptors by increasing their stability within the endoplasmic reticulum.
Gamma-aminobutyric acid receptors (GABA(A)R) are the major sites of fast inhibitory neurotransmission in the brain, and a critical determinant for the efficacy of neuronal inhibition is the number of these receptors that are expressed on the neuronal cell surface. GABA(A)Rs are heteropentamers that can be constructed from seven subunit classes with multiple members; alpha, beta, gamma(1-3), delta, epsilon(1-3), theta, and pi. Receptor assembly occurs within the endoplasmic reticulum, and it is evident that transport-competent combinations exiting this organelle can access the cell surface, whereas unassembled subunits are ubiquitinated and subject to proteasomal degradation. In a previous report the ubiquitin-like protein Plic-1 was shown to directly interact with GABA(A)Rs and promote their accumulation at the cell surface. In this study we explore the mechanisms by which Plic-1 regulates the membrane trafficking of GABA(A)Rs. Using both recombinant and neuronal preparations it was apparent that Plic-1 increased the stability of endoplasmic reticulum resident GABA(A)Rs together with an increase in the abundance of poly-ubiquitinated receptor subunits. Furthermore, Plic-1 elevated cell surface expression levels by selectively increasing their rates of membrane insertion. Thus, Plic-1 may play a significant role in regulating the strength of synaptic inhibition by increasing the stability of GABA(A)Rs within the secretory pathway and thereby promoting their insertion into the neuronal plasma membrane.
Saliba
Richard S
RS
Department of Neuroscience, University of Pennsylvania, Philadelphia, Pennsylvania 19104, USA.
Pangalos
Menelas
M
Moss
Stephen J
SJ
D048868:Adaptor Proteins, Signal Transducing; D000071183:Autophagy-Related Proteins; D001921:Brain / Q000378:metabolism*; D002352:Carrier Proteins / Q000235:genetics / Q000378:metabolism*; D018797:Cell Cycle Proteins / Q000235:genetics / Q000378:metabolism*; D002460:Cell Line; D002462:Cell Membrane / Q000235:genetics / Q000378:metabolism*; D004721:Endoplasmic Reticulum / Q000235:genetics / Q000378:metabolism*; D005786:Gene Expression Regulation / Q000502:physiology; D006801:Humans; D009474:Neurons / Q000378:metabolism*; D021122:Protein Subunits / Q000235:genetics / Q000378:metabolism; D021381:Protein Transport / Q000502:physiology; D011963:Receptors, GABA-A / Q000235:genetics / Q000378:metabolism*; D011994:Recombinant Proteins / Q000235:genetics / Q000378:metabolism; D054875:Ubiquitination / Q000502:physiology*
D048868:Adaptor Proteins, Signal Transducing; D000071183:Autophagy-Related Proteins; D002352:Carrier Proteins; D018797:Cell Cycle Proteins; D021122:Protein Subunits; D011963:Receptors, GABA-A; D011994:Recombinant Proteins; C107792:UBQLN1 protein, human