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The inhibition effect of uncarialin A on voltage-dependent L-type calcium channel subunit alpha-1C: Inhibition potential and molecular stimulation
- Source :
- International Journal of Biological Macromolecules. 159:1022-1030
- Publication Year :
- 2020
- Publisher :
- Elsevier BV, 2020.
-
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.
- Subjects :
- Male
Vascular smooth muscle
Contraction (grammar)
Calcium Channels, L-Type
Endothelium
Vasodilator Agents
Myocytes, Smooth Muscle
CHO Cells
02 engineering and technology
Pharmacology
Biochemistry
Rats, Sprague-Dawley
Mice
03 medical and health sciences
Alkaloids
Cricetulus
Structural Biology
Cricetinae
medicine
Animals
L-type calcium channel
Molecular Biology
Phenylephrine
Mesenteric arteries
Cells, Cultured
030304 developmental biology
0303 health sciences
Binding Sites
biology
Chemistry
Uncaria rhynchophylla
Calcium channel
General Medicine
Calcium Channel Blockers
021001 nanoscience & nanotechnology
biology.organism_classification
Mesenteric Arteries
Rats
Mice, Inbred C57BL
medicine.anatomical_structure
Uncaria
0210 nano-technology
Drugs, Chinese Herbal
Protein Binding
medicine.drug
Subjects
Details
- ISSN :
- 01418130
- Volume :
- 159
- Database :
- OpenAIRE
- Journal :
- International Journal of Biological Macromolecules
- Accession number :
- edsair.doi.dedup.....291bc5e6915c312cdf325ded74c3dbda