Yang Philemon S, Alseikhan Badr A, Hiel Hakim, Grant Lisa, Mori Masayuki X, Yang Wanjun, Fuchs Paul A, Yue David T
Ca2+ Signals Laboratory, Department of Biomedical Engineering, Johns Hopkins University School of Medicine, Baltimore, Maryland 21205, USA.
J Neurosci. 2006 Oct 18;26(42):10677-89. doi: 10.1523/JNEUROSCI.3236-06.2006.
Ca(V)1.3 channels comprise a vital subdivision of L-type Ca2+ channels: Ca(V)1.3 channels mediate neurotransmitter release from auditory inner hair cells (IHCs), pancreatic insulin secretion, and cardiac pacemaking. Fitting with these diverse roles, Ca(V)1.3 channels exhibit striking variability in their inactivation by intracellular Ca2+. IHCs show generally weak-to-absent Ca2+-dependent inactivation (CDI), potentially permitting audition of sustained sounds. In contrast, the strong CDI seen elsewhere likely provides critical negative feedback. Here, we explore this mysterious CDI malleability, particularly its comparative weakness in hair cells. At baseline, heterologously expressed Ca(V)1.3 channels exhibit intense CDI, wherein each lobe of calmodulin (CaM) contributes a distinct inactivation component. Because CaM-like molecules (bearing four recognizable but not necessarily functional Ca2+-binding EF hands) can perturb the Ca2+ response of molecules regulated by CaM, we asked whether such CaM-like entities could influence CDI. We find that CaM-like calcium-binding protein (CaBP) molecules are clearly expressed within the organ of Corti. In particular, the rare subtype CaBP4 is specific to IHCs, and CaBP4 proves capable of eliminating even the potent baseline CDI of Ca(V)1.3. CaBP4 thereby represents a plausible candidate for moderating CDI within IHCs.
Ca(V)1.3通道是L型Ca2+通道的一个重要亚类：Ca(V)1.3通道介导听觉内毛细胞（IHC）释放神经递质、胰腺胰岛素分泌以及心脏起搏。与这些多样的功能相契合，Ca(V)1.3通道在细胞内Ca2+介导的失活方面表现出显著的变异性。IHC通常显示出较弱至几乎没有Ca2+依赖性失活（CDI），这可能使它们能够感知持续的声音。相比之下，在其他地方观察到的强烈CDI可能提供关键的负反馈。在这里，我们探究这种神秘的CDI可塑性，特别是其在毛细胞中相对较弱的特性。在基线状态下，异源表达的Ca(V)1.3通道表现出强烈的CDI，其中钙调蛋白（CaM）的每个叶都贡献一个独特的失活成分。由于类似CaM的分子（带有四个可识别但不一定具有功能的Ca2+结合EF手）可以干扰受CaM调节的分子的Ca2+反应，我们询问这种类似CaM的实体是否会影响CDI。我们发现类似CaM的钙结合蛋白（CaBP）分子在柯蒂氏器中明显表达。特别是，罕见的亚型CaBP4对IHC具有特异性，并且CaBP4能够消除Ca(V)1.3甚至强大的基线CDI。因此，CaBP4是调节IHC内CDI的一个合理候选分子。
