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.

Abstract

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*

Substances

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