Niemeyer B A, Bergs C, Wissenbach U, Flockerzi V, Trost C
Institut für Pharmakologie und Toxikologie der Universität des Saarlandes, 66421 Homburg, Germany.
Proc Natl Acad Sci U S A. 2001 Mar 13;98(6):3600-5. doi: 10.1073/pnas.051511398.
A finely tuned Ca(2+) signaling system is essential for cells to transduce extracellular stimuli, to regulate growth, and to differentiate. We have recently cloned CaT-like (CaT-L), a highly selective Ca(2+) channel closely related to the epithelial calcium channels (ECaC) and the calcium transport protein CaT1. CaT-L is expressed in selected exocrine tissues, and its expression also strikingly correlates with the malignancy of prostate cancer. The expression pattern and selective Ca(2+) permeation properties suggest an important function in Ca(2+) uptake and a role in tumor progression, but not much is known about the regulation of this subfamily of ion channels. We now demonstrate a biochemical and functional mechanism by which cells can control CaT-L activity. CaT-L is regulated by means of a unique calmodulin binding site, which, at the same time, is a target for protein kinase C-dependent phosphorylation. We show that Ca(2+)-dependent calmodulin binding to CaT-L, which facilitates channel inactivation, can be counteracted by protein kinase C-mediated phosphorylation of the calmodulin binding site.
一个精细调节的Ca(2+)信号系统对于细胞传导细胞外刺激、调节生长和分化至关重要。我们最近克隆了CaT样（CaT-L），一种与上皮钙通道（ECaC）和钙转运蛋白CaT1密切相关的高度选择性Ca(2+)通道。CaT-L在特定的外分泌组织中表达，其表达也与前列腺癌的恶性程度显著相关。其表达模式和选择性Ca(2+)通透特性表明其在Ca(2+)摄取中具有重要功能，并在肿瘤进展中发挥作用，但对于这个离子通道亚家族的调节知之甚少。我们现在证明了一种细胞可以控制CaT-L活性的生化和功能机制。CaT-L通过一个独特的钙调蛋白结合位点进行调节，该位点同时也是蛋白激酶C依赖性磷酸化的靶点。我们表明，依赖Ca(2+)的钙调蛋白与CaT-L的结合促进通道失活，而蛋白激酶C介导的钙调蛋白结合位点磷酸化可以抵消这种结合。
