Nature Neuroscience 与耳聋和心律失常有关的钙离子通道功能

Nature Neuroscience ：与耳聋和心律失常有关的钙离子通道功能

研究人员发现，一种钙离子通道功能的缺失不仅与人类耳聋有关，而且与心律失常有关，新成果发表在12月在线出版的Nature Neuroscience 期刊上。新发现为理解人类的听力和耳聋提供了新见解，并强调进行心脏测试以预防耳聋的必要性，尽管耳聋的确切原因尚不完全清楚。

L型钙离子通道是一种能让钙离子进入细胞的特别离子通道，它对听觉毛细胞功能和窦房结功能都至关重要，窦房结是影响心脏节律的关键。

基因CACNA1D是一种参与编码L型钙离子通道中小孔形成的基因。Hanno  Bolz和同事合作，在诸多血亲关系亲戚都是耳聋的两个家族中，鉴别出  CACNA1D的一种变异。

所有的耳聋患者都表现出显著的窦房结功能紊乱，并在休息时伴随有不正常的心跳减慢。对这种变异钙离子通道的深入研究发现，变异导致钙离子不能穿过通道，而这种变异钙离子通道功能的缺失总是与听觉和窦房结细胞的电兴奋性的变化联系在一起，这两种变化则是耳聋患者失聪和窦房结功能紊乱的原因。

推荐原文出处：

Nature Neuroscience   doi:10.1038/nn.2694

Loss of Cav1.3 (CACNA1D) function in a human channelopathy with bradycardia and congenital deafness

Shahid M Baig,Alexandra Koschak,Andreas Lieb,Mathias Gebhart,Claudia Dafinger,Gudrun Nürnberg,Amjad Ali,Ilyas Ahmad,Martina J Sinnegger-Brauns,Niels Brandt,Jutta Engel,Matteo E Mangoni,Muhammad Farooq,Habib U Khan,Peter Nürnberg,J?rg Striessnig& Hanno J Bolz

Deafness is genetically very heterogeneous and forms part of several syndromes. So far, delayed rectifier potassium channels have been linked to human deafness associated with prolongation of the QT interval on electrocardiograms and ventricular arrhythmia in Jervell and Lange-Nielsen syndrome. Cav1.3 voltage-gated L-type calcium channels (LTCCs) translate sound-induced depolarization into neurotransmitter release in auditory hair cells and control diastolic depolarization in the mouse sinoatrial node (SAN). Human deafness has not previously been linked to defects in LTCCs. We used positional cloning to identify a mutation in CACNA1D, which encodes the pore-forming α1 subunit of Cav1.3 LTCCs, in two consanguineous families with deafness. All deaf subjects showed pronounced SAN dysfunction at rest. The insertion of a glycine residue in a highly conserved, alternatively spliced region near the channel pore resulted in nonconducting calcium channels that had abnormal voltage-dependent gating. We describe a human channelopathy (termed SANDD syndrome, sinoatrial node dysfunction and deafness) with a cardiac and auditory phenotype that closely resembles that of Cacna1d?/? mice.