School of Biomedical Sciences, Faculty of Medicine, The University of Queensland, St Lucia, QLD 4072, Australia
School of Biomedical Sciences, Faculty of Medicine, The University of Queensland, St Lucia, QLD 4072, Australia.
Proc Natl Acad Sci U S A. 2021 Feb 23;118(8). doi: 10.1073/pnas.2021581118.
Acid-sensing ion channels (ASICs) are expressed in the nervous system, activated by acidosis, and implicated in pain pathways. Mambalgins are peptide inhibitors of ASIC1 and analgesic in rodents via inhibition of centrally expressed ASIC1a and peripheral ASIC1b. This activity has generated interest in mambalgins as potential therapeutics. However, most mechanism and structure-activity relationship work on mambalgins has focused on ASIC1a, and neglected the peripheral analgesic target ASIC1b. Here, we compare mambalgin potency and mechanism of action at heterologously expressed rat and human ASIC1 variants. Unlike the nanomolar inhibition at ASIC1a and rodent ASIC1b, we find mambalgin-3 only weakly inhibits human ASIC1b and ASIC1b/3 under severe acidosis, but potentiates currents under mild/moderate acidosis. Our data highlight the importance of understanding the activity of potential ASIC-targeting pharmaceuticals at human channels.
酸敏离子通道（ASICs）在神经系统中表达，被酸化激活，并与疼痛途径有关。Mambalgins 是 ASIC1 的肽抑制剂，通过抑制中枢表达的 ASIC1a 和外周 ASIC1b 在啮齿动物中具有镇痛作用。这种活性使 mambalgins 作为潜在治疗药物引起了人们的兴趣。然而，大多数关于 mambalgins 的机制和构效关系研究都集中在 ASIC1a 上，而忽略了外周镇痛靶点 ASIC1b。在这里，我们比较了异源表达的大鼠和人 ASIC1 变体中 mambalgin 的效力和作用机制。与在 ASIC1a 和啮齿动物 ASIC1b 上的纳摩尔抑制作用不同，我们发现 mambalgin-3 仅在严重酸中毒下微弱抑制人 ASIC1b 和 ASIC1b/3，但在轻度/中度酸中毒下增强电流。我们的数据强调了在人类通道中理解潜在 ASIC 靶向药物活性的重要性。
