科研之友
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摘要
Hyperekplexia, an inherited neuronal disorder characterized by exaggerated startle responses with unexpected sensory stimuli, is caused by dysfunction of glycinergic inhibitory transmission. From analysis of newly identified human hyperekplexia mutations in the glycine receptor (GlyR) alpha 1 subunit, we found that an alanine-to-proline missense mutation (A384P) resulted in substantially higher desensitization level and lower agonist sensitivity of homomeric alpha 1 GlyRs when expressed in HEK cells. The incorporation of the beta subunit fully reversed the reduction in agonist sensitivity and partially reversed the desensitization of alpha 1(A384P). The heteromeric alpha 1(A384P) beta GlyRs showed enhanced desensitization but unchanged agonist-induced maximum responses, surface expression, main channel conductance, and voltage dependence compared with that of the wild-type alpha 1 beta (alpha 1(WT)beta) GlyRs. Coexpression of the R392H and A384P mutant alpha 1 subunits, which mimic the expression of the compound heterozygous mutation in a hyperekplexia patient, resulted in channel properties similar to those with alpha 1(A384P) subunit expression alone. In comparison, another human hyperekplexia mutation alpha 1(P250T), which was previously reported to enhance desensitization, caused a strong reduction in maximum currents in addition to the altered desensitization. These results were further confirmed by overexpression of alpha 1(P250T) or alpha 1(A384P) subunits in cultured neurons isolated from SD rats of either sex. Moreover, the IPSC-like responses of cells expressing alpha 1(A384P) beta induced by repeated glycine pulses showed a stronger frequency-dependent reduction than those expressing alpha 1(WT) beta. Together, our findings demonstrate that A384 is associated with the desensitization site of the alpha 1 subunit and its proline mutation produced enhanced desensitization of GlyRs, which contributes to the pathogenesis of human hyperekplexia.
- 出版日期2018-3-14
- 单位中国医科大学
