Dextromethorphan and Dextrorphan Influence Insulin Secretion by Interacting with KATP and L-type Ca2+ Channels in Pancreatic β-Cells

J Pharmacol Exp Ther. 2020 Oct;375(1):10-20. doi: 10.1124/jpet.120.265835. Epub 2020 Jul 14.

Abstract

The NMDA receptor antagonist dextromethorphan (DXM) and its metabolite dextrorphan (DXO) have been recommended for treatment of type 2 diabetes mellitus because of their beneficial effects on insulin secretion. This study investigates how different key points of the stimulus-secretion coupling in mouse islets and β-cells are influenced by DXM or DXO. Both compounds elevated insulin secretion, electrical activity, and [Ca2+]c in islets at a concentration of 100 µM along with a stimulating glucose concentration. DXO and DXM increased insulin secretion approximately 30-fold at a substimulatory glucose concentration (3 mM). Patch-clamp experiments revealed that 100 µM DXM directly inhibited KATP channels by about 70%. Of note, DXM decreased the current through L-type Ca2+ channels about 25%, leading to a transient reduction in Ca2+ action potentials. This interaction might explain why elevating DXM to 500 µM drastically decreased insulin release. DXO inhibited KATP channels almost equally. In islets of KATP channel-deficient sulfonylurea receptor 1 knockout mice, the elevating effects of 100 µM DXM on [Ca2+]c and insulin release were completely lost. By contrast, 100 µM DXO still increased glucose-stimulated insulin release around 60%. In summary, DXM-induced alterations in stimulus-secretion coupling of wild-type islets result from a direct block of KATP channels and are partly counteracted by inhibition of L-type Ca2+ channels. The stimulatory effect of DXO seems to be based on a combined antagonism on KATP channels and NMDA receptors and already occurs under resting conditions. Consequently, both compounds seem not to be suitable candidates for treatment of type 2 diabetes mellitus. SIGNIFICANCE STATEMENT: This study shows that the use of dextromethorphan as an antidiabetic drug can cause unpredictable alterations in insulin secretion by direct interaction with KATP and L-type Ca2+ channels besides its actual target, the NMDA receptor.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Calcium Channels, L-Type / metabolism*
  • Cells, Cultured
  • Dextromethorphan / pharmacology*
  • Dextrorphan / pharmacology*
  • Female
  • Glucose / metabolism
  • Hypoglycemic Agents / pharmacology*
  • Insulin Secretion / drug effects*
  • Insulin-Secreting Cells / drug effects*
  • Insulin-Secreting Cells / metabolism
  • KATP Channels / antagonists & inhibitors*
  • KATP Channels / metabolism
  • Male
  • Membrane Potentials / drug effects
  • Mice
  • Mice, Inbred C57BL
  • Mice, Knockout
  • Patch-Clamp Techniques
  • Sulfonylurea Receptors / genetics

Substances

  • Abcc8 protein, mouse
  • Calcium Channels, L-Type
  • Hypoglycemic Agents
  • KATP Channels
  • Sulfonylurea Receptors
  • Dextrorphan
  • Dextromethorphan
  • Glucose