Departamento de Neurología, Escuela de Medicina and Centro Interdisciplinario de Neurociencias, Facultad de Medicina, Pontificia Universidad Católica de Chile, Marcoleta 391, Santiago, Chile.
Institute of Biomedical Sciences, Faculty of Health Sciences, Universidad Autónoma de Chile, Santiago, Chile.
Biol Res. 2023 Oct 25;56(1):56. doi: 10.1186/s40659-023-00468-9.
Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) causes the ongoing coronavirus disease 2019 (COVID-19). An aspect of high uncertainty is whether the SARS-CoV-2 per se or the systemic inflammation induced by viral infection directly affects cellular function and survival in different tissues. It has been postulated that tissue dysfunction and damage observed in COVID-19 patients may rely on the direct effects of SARS-CoV-2 viral proteins. Previous evidence indicates that the human immunodeficiency virus and its envelope protein gp120 increase the activity of connexin 43 (Cx43) hemichannels with negative repercussions for cellular function and survival. Here, we evaluated whether the spike protein S1 of SARS-CoV-2 could impact the activity of Cx43 hemichannels.
We found that spike S1 time and dose-dependently increased the activity of Cx43 hemichannels in HeLa-Cx43 cells, as measured by dye uptake experiments. These responses were potentiated when the angiotensin-converting enzyme 2 (ACE2) was expressed in HeLa-Cx43 cells. Patch clamp experiments revealed that spike S1 increased unitary current events with conductances compatible with Cx43 hemichannels. In addition, Cx43 hemichannel opening evoked by spike S1 triggered the release of ATP and increased the [Ca] dynamics elicited by ATP.
We hypothesize that Cx43 hemichannels could represent potential pharmacological targets for developing therapies to counteract SARS-CoV-2 infection and their long-term consequences.
严重急性呼吸综合征冠状病毒 2（SARS-CoV-2）引起持续的 2019 年冠状病毒病（COVID-19）。一个高度不确定的方面是，SARS-CoV-2 本身还是病毒感染引起的全身炎症是否直接影响不同组织中的细胞功能和存活。有人推测，COVID-19 患者中观察到的组织功能障碍和损伤可能依赖于 SARS-CoV-2 病毒蛋白的直接作用。先前的证据表明，人类免疫缺陷病毒及其包膜蛋白 gp120 增加了连接蛋白 43（Cx43）半通道的活性，对细胞功能和存活产生负面影响。在这里，我们评估了 SARS-CoV-2 的刺突蛋白 S1 是否会影响 Cx43 半通道的活性。
我们发现，刺突 S1 时间和剂量依赖性地增加了 HeLa-Cx43 细胞中 Cx43 半通道的活性，如染料摄取实验所示。当 HeLa-Cx43 细胞中表达血管紧张素转换酶 2（ACE2）时，这些反应得到增强。膜片钳实验表明，刺突 S1 增加了与 Cx43 半通道电导兼容的单位电流事件。此外，刺突 S1 引发的 Cx43 半通道开放触发了 ATP 的释放，并增加了由 ATP 引发的 [Ca]动力学。
我们假设 Cx43 半通道可能是开发针对 SARS-CoV-2 感染及其长期后果的治疗方法的潜在药理学靶点。
