Shin Josef, Kovacheva Lora, Thomas Dominique, Stojanovic Strahinja, Knowlton Christopher J, Mankel Johanna, Boehm Johannes, Farassat Navid, Paladini Carlos, Striessnig Jörg, Canavier Carmen C, Geisslinger Gerd, Roeper Jochen
Goethe University, Institute of Neurophysiology, Neuroscience Center, Frankfurt am Main, Germany.
Pharmazentrum Frankfurt/ZAFES, Institute of Clinical Pharmacology, Frankfurt am Main, Germany.
Sci Adv. 2022 Jun 10;8(23):eabm4560. doi: 10.1126/sciadv.abm4560. Epub 2022 Jun 8.
The low-threshold L-type calcium channel Ca1.3 accelerates the pacemaker rate in the heart, but its functional role for the extended dynamic range of neuronal firing is still unresolved. Here, we show that Ca1.3 calcium channels act as unexpectedly simple, full-range linear amplifiers of firing rates for lateral dopamine substantia nigra (DA SN) neurons in mice. This means that they boost in vitro or in vivo firing frequencies between 2 and 50 hertz by about 30%. Furthermore, we demonstrate that clinically relevant, low nanomolar concentrations of the L-type channel inhibitor isradipine selectively reduce the in vivo firing activity of these nigrostriatal DA SN neurons at therapeutic plasma concentrations. Thus, our study identifies the pacemaker function of neuronal Ca1.3 channels and provides direct evidence that repurposing dihydropyridines such as isradipine is feasible to selectively modulate the in vivo activity of highly vulnerable DA SN subpopulations in Parkinson's disease.
低阈值L型钙通道Ca1.3可加快心脏的起搏速率，但其在神经元放电扩展动态范围中的功能作用仍未明确。在此，我们表明，Ca1.3钙通道对于小鼠黑质侧多巴胺（DA SN）神经元的放电频率而言，是出人意料的简单全范围线性放大器。这意味着它们可使体外或体内2至50赫兹的放电频率提高约30%。此外，我们证明，临床相关的低纳摩尔浓度L型通道抑制剂伊拉地平在治疗性血浆浓度下可选择性降低这些黑质纹状体DA SN神经元的体内放电活性。因此，我们的研究确定了神经元Ca1.3通道的起搏功能，并提供了直接证据，表明重新利用诸如伊拉地平之类的二氢吡啶类药物来选择性调节帕金森病中高度易损DA SN亚群的体内活性是可行的。
