Berberine induces pacemaker potential inhibition via cGMP-dependent ATP-sensitive K+ channels by stimulating mu/delta opioid receptors in cultured interstitial cells of Cajal from mouse small intestine.
Berberine is traditionally used to treat gastrointestinal (GI) motility disorders. The interstitial cells of Cajal (ICCs) are the pacemaker cells of the gastrointestinal tract, which are responsible for the production of gut movements. The present study aimed to investigate the effects of berberine on pacemaker potentials (PPs) in cultured ICC clusters from the mouse small intestine, and sought to identify the receptors involved and the underlying mechanisms of action. All experiments were performed on cultured ICCs, and a whole‑cell patch‑clamp configuration was used to record PPs from ICC clusters (current clamp mode). Under current clamp mode, berberine was shown to decrease the amplitude and frequency of PPs. However, these effects were suppressed by treatment with glibenclamide, a specific ATP‑sensitive K+ channel blocker. Nor‑binaltorphimine dihydrochloride (a kappa opioid receptor antagonist) did not suppress berberine‑induced PP inhibition, whereas ICI 174,864 (a delta opioid receptor antagonist) and CTOP (a mu opioid receptor antagonist) did suppress the inhibitory effects of berberine. Pretreatment with SQ‑22536 (an adenylate cyclase inhibitor) or with KT‑5720 (a protein kinase A inhibitor) did not suppress the effects of berberine; however, pretreatment with 1H‑[1,2,4] oxadiazolo [4,3‑a] quinoxalin‑1‑one (a guanylate cyclase inhibitor) or KT‑5823 [a protein kinase G (PKG) inhibitor] did. In addition, berberine stimulated cyclic guanosine monophosphate (cGMP) production in ICCs. These observations indicate that berberine may inhibit the pacemaker activity of ICC clusters via ATP‑sensitive K+ channels and the cGMP‑PKG‑dependent pathway by stimulating mu and delta opioid receptors. Therefore, berberine may provide a basis for the development of novel agents for the treatment of GI motility dysfunction.
Division of Longevity and Biofunctional Medicine, Pusan National University School of Korean Medicine, Yangsan, Gyeongsangnam‑do 50612, Republic of Korea.
Hyun Jung
HJ
Kim
Division of Pharmacology, Pusan National University School of Korean Medicine, Yangsan, Gyeongsangnam‑do 50612, Republic of Korea.
Hyungwoo
H
Kim
Division of Longevity and Biofunctional Medicine, Pusan National University School of Korean Medicine, Yangsan, Gyeongsangnam‑do 50612, Republic of Korea.
Myeong Ho
MH
Jung
Division of Longevity and Biofunctional Medicine, Pusan National University School of Korean Medicine, Yangsan, Gyeongsangnam‑do 50612, Republic of Korea.
Young Kyu
YK
Kwon
Division of Longevity and Biofunctional Medicine, Pusan National University School of Korean Medicine, Yangsan, Gyeongsangnam‑do 50612, Republic of Korea.
Byung Joo
BJ
Kim
D000818:Animals; D000890:Anti-Infective Agents / Q000494:pharmacology; D000930:Antidiarrheals / Q000494:pharmacology*; D001599:Berberine / Q000737:chemistry / Q000494:pharmacology*; D028142:Berberis / Q000737:chemistry; D002478:Cells, Cultured; D006152:Cyclic GMP / Q000378:metabolism*; D017869:Cyclic GMP-Dependent Protein Kinases / Q000378:metabolism; D006162:Guanylate Cyclase / Q000378:metabolism; D056885:Interstitial Cells of Cajal / Q000166:cytology / Q000187:drug effects* / Q000378:metabolism; D007421:Intestine, Small / Q000166:cytology / Q000187:drug effects / Q000378:metabolism; D054086:KATP Channels / Q000378:metabolism*; D051379:Mice; D008807:Mice, Inbred BALB C; D017465:Receptors, Opioid, delta / Q000378:metabolism*; D017450:Receptors, Opioid, mu / Q000378:metabolism*
D000890:Anti-Infective Agents; D000930:Antidiarrheals; D054086:KATP Channels; D017465:Receptors, Opioid, delta; D017450:Receptors, Opioid, mu; D001599:Berberine; D017869:Cyclic GMP-Dependent Protein Kinases; D006162:Guanylate Cyclase; D006152:Cyclic GMP