Bisphosphonates stimulate an endogenous nonselective cation channel in Xenopus oocytes: potential mechanism of action

Area of Science:

• Pharmacology
• Molecular Biology
• Ion Channel Physiology

Background:

• Bisphosphonates (BPs) are widely used to treat bone diseases, but their precise mechanisms of action remain unclear.
• Beyond their known effects on osteoclasts, BPs have been implicated in gastrointestinal complications and interactions with ion channels.
• Recent evidence suggests BPs influence preparations expressing the epithelial sodium channel (ENaC).

Purpose of the Study:

• To investigate the effects of bisphosphonates on ion channel function, specifically focusing on the epithelial sodium channel (ENaC).
• To elucidate the role of endogenous ion conductances and their modulation by aminobisphosphonates.

Main Methods:

• Utilized the Xenopus oocyte expression system to study ion channel activity.
• Applied alendronate and risedronate to oocytes and measured changes in endogenous nonselective cation conductance (NSCC) and ENaC activity.
• Investigated the influence of extracellular pH, genistein, and tyrosine phosphatase inhibitors on BP-induced channel modulation.

Main Results:

• Alendronate and risedronate significantly stimulated an endogenous NSCC in Xenopus oocytes, an effect blocked by extracellular acidification.
• Alendronate demonstrated a modest inhibition of ENaC conductance, more pronounced at pH 6.4.
• BP-induced NSCC stimulation involved the tyrosine kinase pathway, as indicated by augmentation with genistein and inhibition by a tyrosine phosphatase inhibitor.

Conclusions:

• Bisphosphonates, particularly aminobisphosphonates, modulate endogenous ion conductances and ENaC activity in a pH-dependent manner.
• The stimulation of NSCC by BPs may lead to membrane depolarization, contributing to their osteoclast inhibitory effects.
• These findings provide new insights into the molecular mechanisms underlying bisphosphonate action and potential side effects.