Recessive hyperekplexia mutations of the glycine receptor α1 subunit affect cell surface integration and stability

摘要: The human neurological disorder hyperekplexia is frequently caused by recessive and dominant mutations of the glycine receptor alpha1 subunit gene, GLRA1. Dominant forms are mostly attributed to amino acid substitutions within ion pore or adjacent loops, resulting in altered channel properties. Here, biogenesis mutants underlying was analyzed following recombinant expression HEK293 cells. mutant S231R resulted a decrease surface integrated protein, consistent with reduced maximal current values. Decreased currents shown for I244N were associated protein instability, rather than decreased integration. R252H R392H encode exchanges arginine residues delineating intracellular faces transmembrane domains. After expression, virtually absent from cell surface, non-functionality importance positive charge membrane Surface highly reduced, residual chloride conductance. Independent site mutation polypeptide, metabolic radiolabelling pulse chase studies revealed shorter half-life full-length all as compared wild-type. Treatment proteasome blocker, lactacystin, significantly increased accumulation membranes. These observations indicated that recognized endoplasmatic reticulum control system, degraded via pathway. Thus, lack glycinergic inhibition may be sequestration subunits quality system.