The inhibition effect of uncarialin A on voltage-dependent L-type calcium channel subunit alpha-1C: Inhibition potential and molecular stimulation

Int J Biol Macromol. 2020 Sep 15;159:1022-1030. doi: 10.1016/j.ijbiomac.2020.05.100. Epub 2020 May 16.


Cardiovascular diseases, such as hypertension and cardiac failure, have become the most major and global cause for threatening human health in recent years. Uncaria rhynchophylla as a traditional Chinese medicine is widely used to treat hypertension for a long history, whereas its medicinal effective components and potential action mechanism are uncertain. Therefore, twenty-four alkaloids (1-24) isolated from U. rhynchophylla were assayed for their relaxant effects against phenylephrine (Phe)-induced contraction of rat mesenteric arteries. Among them, we surprisingly found that uncarialin A (21) exhibited most potent relaxation effect against Phe-induced contraction (IC50 = 0.18 μM) in the manner of independent on endothelium-derived vasorelaxing factors and endothelium. All the experiments including measurement of Ca2+ in vascular smooth muscle cells (VSMCs) by fluorescence microscopy, whole-cell path clamp, molecular docking, and molecular dynamics, demonstrated that uncarialin A (21) could significantly inhibit L-type calcium channel subunit alpha-1C (Cav1.2) via the hydrogen bond interaction with amino acid residue Met1186, allowing the inhibition of Ca2+ inward current. Our results suggested that uncarialin A (21) could be served as a potential L-type Cav1.2 blocker in the effective treatment of cardiovascular diseases.

Keywords: L-type calcium channel subunit alpha-1C; Mesenteric artery; Molecular docking; Molecular dynamics; Relaxation; Uncarialin A.

MeSH terms

  • Alkaloids / analysis
  • Animals
  • Binding Sites
  • CHO Cells
  • Calcium Channel Blockers / chemistry
  • Calcium Channel Blockers / pharmacology*
  • Calcium Channels, L-Type / chemistry
  • Calcium Channels, L-Type / metabolism*
  • Cells, Cultured
  • Cricetinae
  • Cricetulus
  • Drugs, Chinese Herbal / chemistry*
  • Male
  • Mesenteric Arteries / drug effects
  • Mice
  • Mice, Inbred C57BL
  • Myocytes, Smooth Muscle / drug effects
  • Protein Binding
  • Rats
  • Rats, Sprague-Dawley
  • Uncaria / chemistry
  • Vasodilator Agents / chemistry
  • Vasodilator Agents / pharmacology*


  • Alkaloids
  • Calcium Channel Blockers
  • Calcium Channels, L-Type
  • Drugs, Chinese Herbal
  • Vasodilator Agents
  • gou-teng