mRNA surveillance and endoplasmic reticulum quality control processes alter biogenesis of mutant GABAA receptor subunits associated with genetic epilepsies

• Published in: Epilepsia (Copenhagen) Vol. 53; no. s9; pp. 59 - 70
• Main Authors: Macdonald, Robert L., Kang, Jing-Qiong
• Format: Journal Article
• Language: English
• Published: Oxford, UK Blackwell Publishing Ltd 01.12.2012
• Subjects: Animals; Channelopathies - genetics; Channelopathies - metabolism; Codon, Nonsense - genetics; Codon, Nonsense - metabolism; Endoplasmic Reticulum - genetics; Endoplasmic Reticulum - metabolism; Endoplasmic reticulum associated degradation; Endoplasmic reticulum retention; Epilepsy - genetics; Epilepsy - metabolism; Epilepsy, Generalized - genetics; Epilepsy, Generalized - metabolism; Frameshift Mutation; GABAA receptors; Humans; Idiopathic generalized epilepsies; Ion Channels - biosynthesis; Mutation; Nonsense mediated decay; Premature translation-termination codons; Proteostasis Deficiencies - genetics; Proteostasis Deficiencies - metabolism; Receptors, GABA-A - biosynthesis; Receptors, GABA-A - genetics; RNA Splicing; RNA, Messenger - metabolism; Unfolded protein response
• ISSN: 0013-9580; 1528-1167; 1528-1167
• DOI: 10.1111/epi.12035

Summary Previous studies from our and other groups have demonstrated that the majority of γ‐aminobutyric acid (GABA)A receptor subunit mutations produce mutant subunits with impaired biogenesis and trafficking. These GABAA receptor mutations include missense, nonsense, deletion, or insertion mutations that result in a frameshift with premature translation‐termination codons (PTCs) and splice‐site mutations. Frameshift or splice‐site mutations produce mutant proteins with PTCs, thus generating nonfunctional truncated proteins. All of these mutant GABAA receptor subunits are subject to cellular quality control at the messenger RNA (mRNA) or protein level. These quality‐control checkpoints shape the cell’s response to the presence of the mutant subunits and attempt to reduce the impact of the mutant subunit on GABAA receptor expression and function. The check points prevent nonfunctioning or malfunctioning GABAA receptor subunits from trafficking to the cell surface or to synapses, and help to ensure that the receptor channels trafficked to the membrane and synapses are indeed functional. However, if and how these quality control or check points impact the posttranslational modifications of functional GABAA receptor channels such as receptor phosphorylation and ubiquitination and their involvement in mediating GABAergic inhibitory synaptic strength needs to be investigated in the near future.