Fukuoka Ryo, Yano Yusuke, Hara Nozomi, Sadamoto Chihiro, Maturana Andres D, Kita Masaki
Department of Applied Biosciences, Graduate School of Bioagricultural Sciences, Nagoya University, Furo-cho, Chikusa, Nagoya, 464-8601, Japan.
Promotion Office for Open Innovation, Institutes of Innovation for Future Society, Nagoya University, Furo-cho, Chikusa, Nagoya, 464-8601, Japan.
Angew Chem Int Ed Engl. 2025 Jul;64(27):e202503891. doi: 10.1002/anie.202503891. Epub 2025 May 2.
Mammalian secreted venoms mainly consist of peptides and proteases used for defense or predation. Blarina paralytic peptides (BPPs), mealworm-targeting neurotoxins from shrew, are very similar to human synenkephalin. This peptide is released from proenkephalin in the brain along with opioid peptides that mediate analgesic and antidepressant effects, though its physiological function is unclear. Here, we synthesized and characterized human synenkephalin [1-53] (hSYN) and reveal its disulfide bond connectivity. Similar to BPP2, hSYN caused a hyperpolarizing shift in the human T-type voltage-gated calcium channel (hCa3.2) at 0.74 µM, but did not paralyze mealworms. Molecular docking and molecular dynamics simulations showed that hSYN and BPP2 interact with hCa3.2 channel differently, due to differences in polar residues. Since Ca3.2 channel regulates neuronal excitability and is implicated in conditions like autism and epilepsy, our findings on hSYN could provide insight into the channel gating and agonistic mechanisms, along with potential pathways for developing treatments for neurological disorders.
哺乳动物分泌的毒液主要由用于防御或捕食的肽和蛋白酶组成。短尾鼩针对黄粉虫的神经毒素——白腹鼠麻痹肽（BPPs），与人类脑啡肽非常相似。这种肽在大脑中与介导镇痛和抗抑郁作用的阿片肽一起从脑啡肽原中释放出来，但其生理功能尚不清楚。在这里，我们合成并表征了人类脑啡肽[1-53]（hSYN），并揭示了其二硫键连接方式。与BPP2相似，hSYN在0.74µM时会使人类T型电压门控钙通道（hCa3.2）发生超极化偏移，但不会使黄粉虫麻痹。分子对接和分子动力学模拟表明，由于极性残基的差异，hSYN和BPP2与hCa3.2通道的相互作用方式不同。由于Ca3.2通道调节神经元兴奋性，并与自闭症和癫痫等疾病有关，我们对hSYN的研究结果可以为通道门控和激动机制提供见解，以及为开发神经疾病治疗方法提供潜在途径。
