Hyperpolarization Modulation of the T‐Type hCa _v 3.2 Channel by Human Synenkephalin [1–53], a Shrew Neurotoxin Analogue without Paralytic Effects

Abstract 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 (hCa v 3.2) at 0.74 µM, but did not paralyze mealworms. Molecular docking and molecular dynamics simulations showed that hSYN and BPP2 interact with hCa v 3.2 channel differently, due to differences in polar residues. Since Ca v 3.2 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.